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  • Monocyte-Derived Cells in Tissue-Resident Memory T Cell Formation
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Kuan-Lun Chu; Nathália V. Batista; Mélanie Girard; Tania H. Watts

    There is currently much interest in how different dendritic cell and macrophage populations contribute to T cell–mediated immunity. Although conventional dendritic cell subsets have received much attention for their role in T cell priming, there is emerging evidence for a role for monocyte-derived APC (MoAPC) in tissue-resident memory T cell (Trm) formation. Cells of the monocyte/macrophage lineage play a key role in providing chemokines and cytokines for the localization, differentiation, and survival of Trm and Trm precursors. In addition, inflammatory MoAPC are the key providers of TNF superfamily costimulatory signals, a signal we refer to as signal 4 for T cell activation. Recent evidence suggests that signal 4 from MoAPC occurs postpriming and substantially increases Trm formation. Key questions remain, such as the Ag dependence of signal 4 and the specific mechanisms by which MoAPC–Trm interactions affect the long-term maintenance of Trm.

    更新日期:2020-01-22
  • Maturation of an Antimicrobial Peptide Inhibits Aeromonas hydrophila Infection in Crayfish
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Bao-Rui Zhao; Yi Zheng; Jie Gao; Xian-Wei Wang

    Rapid synthesis and release of active antimicrobial peptides (AMPs) is an important strategy in innate immune. Processing of the precursor into the active form is a common posttranslational modification of AMPs in mammals. However, in invertebrates, the mechanism of AMP maturation is largely unknown. In the current study, to our knowledge, a novel potential AMP, designated as PcnAMP, was identified because of its significant induction by bacterial infection in the red swamp crayfish (Procambarus clarkii). PcnAMP was cleaved into a short fragment postinfection. Using the purified native peptide, this cleavage was found to be mediated by trypsin after synthesis. Proteolysis produced an N-terminal peptide that exerted the antibacterial function. Although the N-terminal peptide did not show significant similarity to any other sequences, it was predicted to have an overall helical structure and high amphipathicity, both of which are typical features of many AMPs. The N-terminal active peptide exhibited a wide spectrum of antimicrobial activity. Atomic force microscope imaging and flow cytometry analysis showed that treatment with the active form of PcnAMP led to the collapse of the bacterial cell wall and permeabilization of the bacterial cell membrane. Thus, this study provided a new candidate for therapeutic agent development, and revealed new insights into the maturation of AMPs in invertebrates.

    更新日期:2020-01-22
  • Cross-Reactivity with Self-Antigen Tunes the Functional Potential of Naive B Cells Specific for Foreign Antigens
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Holly R. Steach; Blair L. DeBuysscher; Allison Schwartz; Jim Boonyaratanakornkit; Melissa L. Baker; Marti R. Tooley; Nicholas A. Pease; Justin J. Taylor

    Upon Ag exposure, naive B cells expressing BCR able to bind Ag can undergo robust proliferation and differentiation that can result in the production of Ab-secreting and memory B cells. The factors determining whether an individual naive B cell will proliferate following Ag encounter remains unclear. In this study, we found that polyclonal naive murine B cell populations specific for a variety of foreign Ags express high levels of the orphan nuclear receptor Nur77, which is known to be upregulated downstream of BCR signaling as a result of cross-reactivity with self-antigens in vivo. Similarly, a fraction of naive human B cells specific for clinically-relevant Ags derived from respiratory syncytial virus and HIV-1 also exhibited an IgMLOW IgD+ phenotype, which is associated with self-antigen cross-reactivity. Functionally, naive B cells expressing moderate levels of Nur77 are most likely to proliferate in vivo following Ag injection. Together, our data indicate that BCR cross-reactivity with self-antigen is a common feature of populations of naive B cells specific for foreign Ags and a moderate level of cross-reactivity primes individual cells for optimal proliferative responses following Ag exposure.

    更新日期:2020-01-22
  • cDC1 IL-27p28 Production Predicts Vaccine-Elicited CD8+ T Cell Memory and Protective Immunity
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Augustus M. Kilgore; Nathan D. Pennock; Ross M. Kedl

    Although adjuvants and formulations are often either empirically derived, or at best judged by their ability to elicit broad inflammation, it would be ideal if specific innate correlates of adaptive immunity could be identified to set a universally applicable benchmark for adjuvant evaluation. Using an IL-27 reporter transgenic mouse model, we show in this study that conventional type 1 dendritic cell IL-27 production in the draining lymph node 12 h after s.c. vaccination directly correlates with downstream CD8+ T cell memory and protective immunity against infectious challenge. This correlation is robust, reproducible, predictive, entirely unique to vaccine biology, and is the only innate correlate of CD8+ T cell immune memory yet to be identified. Our results provide new insights into the basic biology of adjuvant-elicited cellular immunity and have clear implications for the screening and evaluation of novel adjuvants.

    更新日期:2020-01-22
  • Tolerogenic Dendritic Cells Generated by BAFF Silencing Ameliorate Collagen-Induced Arthritis by Modulating the Th17/Regulatory T Cell Balance
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Yingjie Zhao; Xiaojing Sun; Xuezhi Yang; Bingjie Zhang; Siyu Li; Ping Han; Binbin Zhang; Xinwei Wang; Susu Li; Yan Chang; Wei Wei

    Tolerogenic dendritic cells (tolDCs) have received much attention because of their capacity to restore immune homeostasis. RNA interference techniques have been used in several studies to generate tolDCs by inactivating certain molecules that regulate DC maturation and immunologic function. BAFF is a key B cell survival factor that is not only essential for B cell function but also T cell costimulation, and DCs are the major source of BAFF. In this study, we determined whether BAFF gene silencing in mature DCs could lead to a tolerogenic phenotype as well as the potential therapeutic effect of BAFF-silenced DCs on collagen-induced arthritis (CIA) in mice. Meanwhile, CRISPR/Cas9-mediated BAFF−/− DC2.4 cells were generated to verify the role of BAFF in DC maturation and functionality. BAFF-silenced DCs and BAFF−/− DC2.4 cells exhibited an immature phenotype and functional state. Further, the transplantation of BAFF-silenced DCs significantly alleviated CIA severity in mice, which correlated with a reduction in Th17 populations and increased regulatory T cells. In vitro, BAFF-silenced DCs promoted Foxp3 mRNA and IL-10 expression but inhibited ROR-γt mRNA and IL-17A expression in CD4+ T cells. Together, BAFF-silenced DCs can alleviate CIA, partly by inducing Foxp3+ regulatory T cells and suppressing Th17 subsets. Collectively, BAFF plays an important role in interactions between DCs and T cells, which might be a promising genetic target to generate tolDCs for autoimmune arthritis treatment.

    更新日期:2020-01-22
  • IL-9 Controls Central Nervous System Autoimmunity by Suppressing GM-CSF Production
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Satoshi Yoshimura; Rodolfo Thome; Shingo Konno; Elisabeth R. Mari; Javad Rasouli; Daniel Hwang; Alexandra Boehm; Yanhua Li; Guang-Xian Zhang; Bogoljub Ciric; Abdolmohamad Rostami

    Multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) are inflammatory diseases of the CNS in which Th17 cells play a major role in the disease pathogenesis. Th17 cells that secrete GM-CSF are pathogenic and drive inflammation of the CNS. IL-9 is a cytokine with pleiotropic functions, and it has been suggested that it controls the pathogenic inflammation mediated by Th17 cells, and IL-9R−/− mice develop more severe EAE compared with wild-type counterparts. However, the underlying mechanism by which IL-9 suppresses EAE has not been clearly defined. In this study, we investigated how IL-9 modulates EAE development. By using mice knockout for IL-9R, we show that more severe EAE in IL-9R−/− mice correlates with increased numbers of GM-CSF+ CD4+ T cells and inflammatory dendritic cells (DCs) in the CNS. Furthermore, DCs from IL-9R−/− mice induced more GM-CSF production by T cells and exacerbated EAE upon adoptive transfer than did wild-type DCs. Our results suggest that IL-9 reduces autoimmune neuroinflammation by suppressing GM-CSF production by CD4+ T cells through the modulation of DCs.

    更新日期:2020-01-22
  • Impact of Early Antiretroviral Therapy Initiation on HIV-Specific CD4 and CD8 T Cell Function in Perinatally Infected Children
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Stefano Rinaldi; Suresh Pallikkuth; Mark Cameron; Lesley R. de Armas; Nicola Cotugno; Vinh Dinh; Rajendra Pahwa; Brian Richardson; Shelly R. Saini; Salvatore Rocca; Maria G. Lain; Sion L. Williams; Paolo Palma; Savita Pahwa

    Early initiation of antiretroviral therapy (ART) in vertically HIV-infected children limits the size of the virus reservoir, but whether the time of treatment initiation (TI) can durably impact host immune responses associated with HIV infection is still unknown. This study was conducted in PBMC of 20 HIV-infected virally suppressed children on ART (mean age 9.4 y), classified as early treated (ET; age at ART initiation ≤0.5 y, n = 14) or late treated (LT; age at ART initiation 1–10 y, n = 6). Frequencies and functions of Ag-specific CD4 (CD40L+) and CD8 (CD69+) T cells were evaluated by intracellular IL-2, IFN-γ, and TNF-α production with IL-21 in CD4 or CD107a, granzyme B and perforin in CD8 T cells following stimulation with HIV gp140 protein (ENV) or GAG peptides by multiparameter flow cytometry. ET showed a higher proportion of cytokine-producing ENV- and GAG-specific CD4 and CD8 T cells compared with LT. In particular, ET were enriched in polyfunctional T cells. RNA sequencing analysis showed upregulation of immune activation pathways in LT compared with ET. Our results suggest that timing of TI in HIV-infected children has a long-term and measurable impact on the quality of the HIV-specific T cell immune responses and transcriptional profiles of PBMC, reinforcing the importance of early TI.

    更新日期:2020-01-22
  • Single and Synergistic Effects of Type 2 Cytokines on Eosinophils and Asthma Hallmarks
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Hendrik Beckert; Helen Meyer-Martin; Roland Buhl; Christian Taube; Sebastian Reuter

    The type 2 cytokines IL-5, IL-13, and IL-4 play an important role in the induction and progression of asthma. According to the Global Initiative for Asthma guidelines, blood eosinophil numbers are one marker that helps to guide treatment decisions in patients suffering from severe forms of asthma. Effects of type 2 cytokines were analyzed, alone or in combination, on eosinophils in blood and other compartments and on the development of asthma symptoms. C57BL/6 mice received a single intranasal application of equimolar amounts of IL-5, IL-13, and IL-4, alone or in combination. Numbers, activation state, and migratory behavior of eosinophils in bone marrow (BM), blood, lung, and bronchoalveolar lavage as well as airway hyperresponsiveness and goblet cell metaplasia were evaluated. Only IL-13 was associated with airway eosinophilia, development of airway hyperresponsiveness, and goblet cell metaplasia, without any synergistic effects. IL-5 increased the number of eosinophils in BM and lung tissue but failed to affect structural changes. IL-4 had similar, but weaker, effects to IL-13. Cytokine combinations synergistically affected eosinophils but failed to enhance IL-13–driven effects on lung function or goblet cell metaplasia. IL-5 and IL-13 markedly increased eosinophil numbers locally in lung and airways and distally in blood and BM, whereas IL-5 and IL-4 only increased eosinophils in lung and BM. IL-13 together with IL-4 failed to demonstrate any synergistic effect. These insights into single and combined effects of type 2 cytokines on disease-driving mechanisms could improve understanding of the impact and effectiveness of new therapies in asthma.

    更新日期:2020-01-22
  • Functional Expression of the P2X7 ATP Receptor Requires Eros
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Yuta Ryoden; Toshihiro Fujii; Katsumori Segawa; Shigekazu Nagata

    In response to extracellular ATP, the purinergic receptor P2X7 mediates various biological processes, including phosphatidylserine (PtdSer) exposure, phospholipid scrambling, dye uptake, ion transport, and IL-1β production. A genome-wide CRISPR screen for molecules responsible for ATP-induced PtdSer exposure identified a transmembrane protein, essential for reactive oxygen species (Eros), as a necessary component for P2X7 expression. An Eros-null mouse T cell line lost the ability to expose PtdSer, to scramble phospholipids, and to internalize a dye YO-PRO-1 and Ca2+ ions. Eros-null mutation abolished the ability of an LPS-primed human THP-1 macrophage cell line and mouse bone marrow–derived macrophages to secrete IL-1β in response to ATP. Eros is localized to the endoplasmic reticulum and functions as a chaperone for NADPH oxidase components. Similarly, Eros at the endoplasmic reticulum transiently associated with P2X7 to promote the formation of a stable homotrimeric complex of P2X7. These results indicated that Eros acts as a chaperone not only for NADPH oxidase, but also for P2X7, and contributes to the innate immune reaction.

    更新日期:2020-01-22
  • Ca2+–Calcineurin Axis–Controlled NFAT Nuclear Translocation Is Crucial for Optimal T Cell Immunity in an Early Vertebrate
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Xiumei Wei; Huiying Li; Yu Zhang; Cheng Li; Kang Li; Kete Ai; Jialong Yang

    Calcium ion (Ca2+) is a widespread and primitive second messenger that regulates physiological cell functions in almost all life beings. Ca2+ influx-induced NFAT activation is essential for T cell function and adaptive immunity. However, whether and how Ca2+ signaling modulates T cell immunity in early vertebrates, especially in nontetrapods, remains largely unknown. To address these questions, a Nile tilapia (Oreochromis niloticus) model was employed to investigate the regulation of ancestral T cell immunity by Ca2+–NFAT signaling in jawed fish. In Nile tilapia, an evolutionarily conserved Ca2+–NFAT signaling pathway is involved in the primary adaptive immune response during Streptococcus agalactiae infection. Meanwhile, T cell signals trigger several events along the Ca2+–NFAT axis in this early vertebrate, including Ca2+ influx, calcineurin activation, and NFAT nuclear import. More critically, suppression of Ca2+–NFAT signaling by the calcineurin inhibitor cyclosporine A impairs primordial T cell activation, clonal expansion, and infection clearance. Mechanistically, Nile tilapia NFAT interacts with several other transcription factors for potent gene expression, and T cells in this nontetrapod employ Cabin1 and DYRK1A to regulate NFAT nuclear import and export, respectively. To the best of our knowledge, this study is the first to demonstrate the regulatory mechanism of Ca2+–NFAT signaling on T cell immunity in a nontetrapod species. We suggest that modulation of T cell immunity by Ca2+–NFAT signaling is a primitive strategy that already existed prior to the divergence of bony fish from the tetrapod lineage. The findings of this study provide valuable perspectives for understanding the evolution of adaptive immune system.

    更新日期:2020-01-22
  • CD4+ T Cell–Derived NGAL Modifies the Outcome of Ischemic Acute Kidney Injury
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Sul A Lee; Sanjeev Noel; Johanna T. Kurzhagen; Mohanraj Sadasivam; Phillip M. Pierorazio; Lois J. Arend; Abdel R. Hamad; Hamid Rabb

    CD4+ T cells mediate the pathogenesis of ischemic and nephrotoxic acute kidney injury (AKI). However, the underlying mechanisms of CD4+ T cell–mediated pathogenesis are largely unknown. We therefore conducted unbiased RNA-sequencing to discover novel mechanistic pathways of kidney CD4+ T cells after ischemia compared with normal mouse kidney. Unexpectedly, the lipocalin-2 (Lcn2) gene, which encodes neutrophil gelatinase-associated lipocalin (NGAL) had the highest fold increase (∼60). The NGAL increase in CD4+ T cells during AKI was confirmed at the mRNA level with quantitative real-time PCR and at the protein level with ELISA. NGAL is a potential biomarker for the early detection of AKI and has multiple potential biological functions. However, the role of NGAL produced by CD4+ T cells is not known. We found that ischemic AKI in NGAL knockout (KO) mice had worse renal outcomes compared with wild-type (WT) mice. Adoptive transfer of NGAL-deficient CD4+ T cells from NGAL KO mice into CD4 KO or WT mice led to worse renal function than transfer of WT CD4+ T cells. In vitro–simulated ischemia/reperfusion showed that NGAL-deficient CD4+ T cells express higher levels of IFN-γ mRNA compared with WT CD4+ T cells. In vitro differentiation of naive CD4+ T cells to Th17, Th1, and Th2 cells led to significant increase in Lcn2 expression. Human kidney CD4+ T cell NGAL also increased significantly after ischemia. These results demonstrate an important role for CD4+ T cell NGAL as a mechanism by which CD4+ T cells mediate AKI and extend the importance of NGAL in AKI beyond diagnostics.

    更新日期:2020-01-22
  • Differential Induction of SOCS Isoforms by Leishmania donovani Impairs Macrophage–T Cell Cross-Talk and Host Defense
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Pragya Chandrakar; Naveen Parmar; Albert Descoteaux; Susanta Kar

    Immune evasion strategies adopted by Leishmania donovani involve the exploitation of suppressor of cytokine signaling (SOCS) proteins that are well-known negative regulators of the JAK/STAT pathway. However, the cellular mechanism underpinning the induction of SOCS isoforms and their role in breaching the multilevel regulatory circuit connecting the innate and adaptive arms of immunity are still ambiguous during experimental visceral leishmaniasis. Using bone marrow–derived macrophages (BMMфs) and CD4+ T cells, we observed that L. donovani preferentially upregulates SOCS1 and SOCS3 expression in macrophages and T cells, respectively, whereas the SOCS1 level remains consistently high in BMMфs and SOCS3 expression is pronounced and long lasting in T cells. Consequently, this inhibits STAT1-mediated IL-12 induction in macrophages & STAT4-mediated IFN-γ synthesis in T cells. Mechanistically, PI3K/Akt–mediated SRF activation promotes nuclear translocation and binding of Egr2 to SOCS1 promoter for its early induction in infected BMMфs. Additionally, L. donovani activates IDO/kynurenine/AHR signaling in BMMфs to maintain prolonged SOCS1 expression. Later, PGE2, secreted from infected BMMфs induces cAMP–PKA pathway by binding to the EP2/EP4 receptor of CD4+ T cells, leading to SP1, CREB, and GATA1 activation and SOCS3 expression. Small interfering RNA–mediated silencing of SOCS1 and SOCS3 in macrophage and T cells, respectively, restored IL-12 and IFN-γ cytokine levels and BMMф–T cell interaction. Vivo morpholino–mediated silencing of SOCS1 and SOCS3 resulted in protective cytokine responses, thereby reducing organ parasite burden significantly in L. donovani–infected BALB/c mice. Collectively, our results imply that L. donovani orchestrates different SOCS isoforms to impair macrophage–T cell cross-talk and preserve its own niche.

    更新日期:2020-01-22
  • Tuning Subunit Vaccines with Novel TLR Triagonist Adjuvants to Generate Protective Immune Responses against Coxiella burnetii
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Adrienne P. Gilkes; Tyler J. Albin; Saikat Manna; Medalyn Supnet; Sara Ruiz; Janine Tom; Alexander J. Badten; Aarti Jain; Rie Nakajima; Jiin Felgner; D. Huw Davies; Samuel A. Stetkevich; Albert Zlotnik; Eric Pearlman; Aysegul Nalca; Philip L. Felgner; Aaron P. Esser-Kahn; Amanda M. Burkhardt

    Coxiella burnetii is an obligate intracellular bacterium and the causative agent of Q fever. C. burnetii is considered a potential bioterrorism agent because of its low infectious dose; resistance to heat, drying, and common disinfectants; and lack of prophylactic therapies. Q-Vax, a formalin-inactivated whole-bacteria vaccine, is currently the only prophylactic measure that is protective against C. burnetii infections but is not U.S. Food and Drug Administration approved. To overcome the safety concerns associated with the whole-bacteria vaccine, we sought to generate and evaluate recombinant protein subunit vaccines against C. burnetii. To accomplish this, we formulated C. burnetii Ags with a novel TLR triagonist adjuvant platform, which used combinatorial chemistry to link three different TLR agonists together to form one adjuvanting complex. We evaluated the immunomodulatory activity of a panel of TLR triagonist adjuvants and found that they elicited unique Ag-specific immune responses both in vitro and in vivo. We evaluated our top candidates in a live C. burnetii aerosol challenge model in C56BL/6 mice and found that several of our novel vaccine formulations conferred varying levels of protection to the challenged animals compared with sham immunized mice, although none of our candidates were as protective as the commercial vaccine across all protection criteria that were analyzed. Our findings characterize a novel adjuvant platform and offer an alternative approach to generating protective and effective vaccines against C. burnetii.

    更新日期:2020-01-22
  • Naringenin Enhances the Antitumor Effect of Therapeutic Vaccines by Promoting Antigen Cross-Presentation
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Luoyang Wang; Wenfeng Zeng; Luyao Wang; Zihao Wang; Xiaozhe Yin; Yan Qin; Fayun Zhang; Chunling Zhang; Wei Liang

    Dendritic cells (DCs) can internalize and cross-present exogenous Ags to CD8+ T cells for pathogen or tumor cell elimination. Recently, growing evidences suggest the possible immunoregulatory role of flavonoids through modulating the Ag presentation of DCs. In this study, we report that naringenin, a grapefruit-derived flavonoid, possesses the ability to increase the Ag cross-presentation in both murine DC line DC2.4 as well as bone marrow–derived DCs, and naringenin-induced moderate intracellular oxidative stress that contributed to the disruption of lysosomal membrane enhanced Ag leakage to cytosol and cross-presentation. Moreover, in a murine colon adenocarcinoma model, naringenin induced more CD103+ DCs infiltration into tumor and facilitated the activation of CD8+ T cells and strengthened the performance of therapeutic E7 vaccine against TC-1 murine lung cancer. Our investigations may inspire novel thoughts for vaccine design and open a new field of potential applications of flavonoids as immunomodulators to improve host protection against infection and tumor.

    更新日期:2020-01-22
  • Brucella Infection Regulates Thioredoxin-Interacting Protein Expression to Facilitate Intracellular Survival by Reducing the Production of Nitric Oxide and Reactive Oxygen Species
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Hai Hu; Mingxing Tian; Peng Li; Xiang Guan; Zhengmin Lian; Yi Yin; Wentao Shi; Chan Ding; Shengqing Yu

    Thioredoxin-interacting protein (TXNIP) is a multifunctional protein that functions in tumor suppression, oxidative stress, and inflammatory responses. However, how TXNIP functions during microbial infections is rarely reported. In this study, we demonstrate that Brucella infection decreased TXNIP expression to promote its intracellular growth in macrophages by decreasing the production of NO and reactive oxygen species (ROS). Following Brucella abortus infection, TXNIP knockout RAW264.7 cells produced significantly lower levels of NO and ROS, compared with wild-type RAW264.7 cells. Inducible NO synthase (iNOS) inhibitor treatment reduced NO levels, which resulted in a dose-dependent restoration of TXNIP expression, demonstrating that the expression of TXNIP is regulated by NO. In addition, the expression of iNOS and the production of NO were dependent on the type IV secretion system of Brucella. Moreover, Brucella infection reduced TXNIP expression in bone marrow–derived macrophages and mouse lung and spleen. Knocked down of the TXNIP expression in bone marrow–derived macrophages increased intracellular survival of Brucella. These findings revealed the following: 1) TXNIP is a novel molecule to promote Brucella intracellular survival by reducing the production of NO and ROS; 2) a negative feedback–regulation system of NO confers protection against iNOS-mediated antibacterial effects. The elucidation of this mechanism may reveal a novel host surveillance pathway for bacterial intracellular survival.

    更新日期:2020-01-22
  • IL-10 Impairs Local Immune Response in Lung Granulomas and Lymph Nodes during Early Mycobacterium tuberculosis Infection
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Eileen A. Wong; Stephanie Evans; Carolyn R. Kraus; Kathleen D. Engelman; Pauline Maiello; Walter J. Flores; Anthony M. Cadena; Edwin Klein; Kayla Thomas; Alexander G. White; Chelsea Causgrove; Brianne Stein; Jaime Tomko; Joshua T. Mattila; Hannah Gideon; P. Ling Lin; Keith A. Reimann; Denise E. Kirschner; JoAnne L. Flynn

    Tuberculosis (TB), caused by Mycobacterium tuberculosis, continues to be a major global health problem. Lung granulomas are organized structures of host immune cells that function to contain the bacteria. Cytokine expression is a critical component of the protective immune response, but inappropriate cytokine expression can exacerbate TB. Although the importance of proinflammatory cytokines in controlling M. tuberculosis infection has been established, the effects of anti-inflammatory cytokines, such as IL-10, in TB are less well understood. To investigate the role of IL-10, we used an Ab to neutralize IL-10 in cynomolgus macaques during M. tuberculosis infection. Anti–IL-10–treated nonhuman primates had similar overall disease outcomes compared with untreated control nonhuman primates, but there were immunological changes in granulomas and lymph nodes from anti–IL-10–treated animals. There was less thoracic inflammation and increased cytokine production in lung granulomas and lymph nodes from IL-10–neutralized animals at 3–4 wk postinfection compared with control animals. At 8 wk postinfection, lung granulomas from IL-10–neutralized animals had reduced cytokine production but increased fibrosis relative to control animals. Although these immunological changes did not affect the overall disease burden during the first 8 wk of infection, we paired computational modeling to explore late infection dynamics. Our findings support that early changes occurring in the absence of IL-10 may lead to better bacterial control later during infection. These unique datasets provide insight into the contribution of IL-10 to the immunological balance necessary for granulomas to control bacterial burden and disease pathology in M. tuberculosis infection.

    更新日期:2020-01-22
  • Neutrophils Enhance Their Own Influx to Sites of Bacterial Infection via Endosomal TLR-Dependent Cxcl2 Production
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Germana Lentini; Agata Famà; Carmelo Biondo; Nastaran Mohammadi; Roberta Galbo; Giuseppe Mancuso; Daniela Iannello; Sebastiana Zummo; Miriam Giardina; Giuseppe Valerio De Gaetano; Giuseppe Teti; Concetta Beninati; Angelina Midiri

    The influx of neutrophils to infection sites is a fundamental step in host defenses against the frequent human pathogen group B Streptococcus (GBS) and other extracellular bacteria. Using a mouse model of GBS-induced peritonitis, we show in this study that the chemokines Cxcl1 and Cxcl2 play distinctive roles in enhancing the recruitment and the antibacterial activities of neutrophils in a manner that is linked to differences in the cellular sources of these mediators. Cell depletion experiments demonstrated that neutrophils make a significant contribution to the in vivo production of Cxcl2 but not Cxcl1. In vitro, neutrophils responded weakly to LPS but released high levels of Cxcl2 after stimulation with GBS or other bacteria. Neutrophil-derived Cxcl2 acted in an autocrinous manner to increase its own production and to enhance antibacterial activities, including the release of oxygen radicals. In both neutrophils and macrophages, the production of Cxcl1/2 largely required the presence of functional UNC93B1, a chaperone protein involved in signaling by endosomal TLRs. Moreover, the phenotype of UNC93B1-defective phagocytes could be recapitulated by the simultaneous absence of TLR7, 9, and 13 but not by the absence of individual TLRs. Collectively, our data show that neutrophils recognize Gram-positive and Gram-negative bacteria by means of multiple phagosomal TLRs, resulting in de novo synthesis of Cxcl2, amplification of neutrophil recruitment, and potentiation of their antibacterial activities. These data may be useful to devise alternative therapeutic strategies aimed at enhancing the recruitment and the functional activities of polymorphonuclear leukocytes during infections caused by antibiotic-resistant bacteria.

    更新日期:2020-01-22
  • Mycobacterium tuberculosis Lipoarabinomannan Activates Human Neutrophils via a TLR2/1 Mechanism Distinct from Pam3CSK4
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Jessica S. Hook; Mou Cao; Kayson Weng; Nedha Kinnare; Jessica G. Moreland

    Neutrophils, polymorphonuclear (PMN) leukocytes, play an important role in the early innate immune response to Mycobacterium tuberculosis infection in the lung. Interactions between PMN and mycobacterial lipids impact the activation state of these migrated cells with consequences for the surrounding tissue in terms of resolution versus ongoing inflammation. We hypothesized that lipoarabinomannan from M. tuberculosis (Mtb LAM) would prime human PMN in a TLR2-dependent manner and investigated this with specific comparison with the purified synthetic TLR2 agonists, Pam3CSK4 and FSL-1. In contrast to Pam3CSK4 and FSL-1, we found Mtb LAM did not induce any of the classical PMN priming phenotypes, including enhancement of NADPH oxidase activity, shedding of l-selectin, or mobilization of CD11b. However, exposure of PMN to Mtb LAM did elicit pro- and anti-inflammatory cytokine production and release in a TLR2/1-dependent manner, using the TLR1 single-nucleotide polymorphism rs5743618 (1805G/T) as a marker for TLR2/1 specificity. Moreover, Mtb LAM did not elicit p38 MAPK phosphorylation or endocytosis, although these processes occurred with Pam3CSK4 stimulation, and were necessary for the early priming events to occur. Interestingly, Mtb LAM did not abrogate priming responses elicited by Pam3CSK4. Notably, subfractionation of light membranes from Pam3CSK4 versus Mtb LAM–stimulated cells demonstrated differential patterns of exocytosis. In summary, Mtb LAM activates PMN via TLR2/1, resulting in the production of cytokines but does not elicit early PMN priming responses, as seen with Pam3CSK4. We speculate that the inability of Mtb LAM to prime PMN may be due to differential localization of TLR2/1 signaling.

    更新日期:2020-01-22
  • Regulation of Eosinophil Recruitment and Allergic Airway Inflammation by Tropomyosin Receptor Kinase A
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Mythili Dileepan; Xiao Na Ge; Idil Bastan; Yana G. Greenberg; Yuying Liang; P. Sriramarao; Savita P. Rao

    Eosinophilia is a hallmark of allergic airway inflammation (AAI). Identifying key molecules and specific signaling pathways that regulate eosinophilic inflammation is critical for development of novel therapeutics. Tropomycin receptor kinase A (TrkA) is the high-affinity receptor for nerve growth factor. AAI is associated with increased expression of TrkA by eosinophils; however, the functional role of TrkA in regulating eosinophil recruitment and contributing to AAI is poorly understood. This study identifies, to our knowledge, a novel mechanism of eotaxin-mediated activation of TrkA and its role in regulating eosinophil recruitment by using a chemical-genetic approach to specifically inhibit TrkA kinase activity with 1-NM-PP1 in TrkAF592A–knock-in (TrkA-KI) eosinophils. Blockade of TrkA by 1-NM-PP1 enhanced eosinophil spreading on VCAM-1 but inhibited eotaxin-1 (CCL11)–mediated eosinophil migration, calcium flux, cell polarization, and ERK1/2 activation, suggesting that TrkA is an important player in the signaling pathway activated by eotaxin-1 during eosinophil migration. Further, blockade of matrix metalloprotease with BB-94 inhibited eotaxin-1–induced TrkA activation and eosinophil migration, additively with 1-NM-PP1, indicating a role for matrix metalloproteases in TrkA activation. TrkA inhibition in Alternaria alternata–challenged TrkA-KI mice markedly inhibited eosinophilia and attenuated various features of AAI. These findings are indicative of a distinctive eotaxin-mediated TrkA-dependent signaling pathway, which, in addition to other TrkA-activating mediators, contributes to eosinophil recruitment during AAI and suggests that targeting the TrkA signaling pathway to inhibit eosinophil recruitment may serve as a therapeutic strategy for management of eosinophilic inflammation in allergic airway disease, including asthma.

    更新日期:2020-01-22
  • Antiviral Inflammation during Early Pregnancy Reduces Placental and Fetal Growth Trajectories
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Kelly J. Baines; Amanda M. Rampersaud; Dendra M. Hillier; Mariyan J. Jeyarajah; Grace K. Grafham; Genevieve Eastabrook; James C. Lacefield; Stephen J. Renaud

    Many viruses are detrimental to pregnancy and negatively affect fetal growth and development. What is not well understood is how virus-induced inflammation impacts fetal–placental growth and developmental trajectories, particularly when inflammation occurs in early pregnancy during nascent placental and embryo development. To address this issue, we simulated a systemic virus exposure in early pregnant rats (gestational day 8.5) by administering the viral dsRNA mimic polyinosinic:polycytidylic acid (PolyI:C). Maternal exposure to PolyI:C induced a potent antiviral response and hypoxia in the early pregnant uterus, containing the primordial placenta and embryo. Maternal PolyI:C exposure was associated with decreased expression of the maternally imprinted genes Mest, Sfrp2, and Dlk1, which encode proteins critical for placental growth. Exposure of pregnant dams to PolyI:C during early pregnancy reduced fetal growth trajectories throughout gestation, concomitant with smaller placentas, and altered placental structure at midgestation. No detectable changes in placental hemodynamics were observed, as determined by ultrasound biomicroscopy. An antiviral response was not evident in rat trophoblast stem (TS) cells following exposure to PolyI:C, or to certain PolyI:C-induced cytokines including IL-6. However, TS cells expressed high levels of type I IFNR subunits (Ifnar1 and Ifnar2) and responded to IFN-⍺ by increasing expression of IFN-stimulated genes and decreasing expression of genes associated with the TS stem state, including Mest. IFN-⍺ also impaired the differentiation capacity of TS cells. These results suggest that an antiviral inflammatory response in the conceptus during early pregnancy impacts TS cell developmental potential and causes latent placental development and reduced fetal growth.

    更新日期:2020-01-22
  • TLR2 Dimerization Blockade Allows Generation of Homeostatic Intestinal Macrophages under Acute Colitis Challenge
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Mor Gross-Vered; Liraz Shmuel-Galia; Batya Zarmi; Fiachra Humphries; Christoph Thaiss; Tomer-Meir Salame; Eyal David; Louise Chappell-Maor; Katherine A. Fitzgerald; Yechiel Shai; Steffen Jung

    Recruited blood monocytes contribute to the establishment, perpetuation, and resolution of tissue inflammation. Specifically, in the inflamed intestine, monocyte ablation was shown to ameliorate colitis scores in preclinical animal models. However, the majority of intestinal macrophages that seed the healthy gut are also monocyte derived. Monocyte ablation aimed to curb inflammation would therefore likely interfere with intestinal homeostasis. In this study, we used a TLR2 trans-membrane peptide that blocks TLR2 dimerization that is critical for TLR2/1 and TLR2/6 heterodimer signaling to blunt inflammation in a murine colitis model. We show that although the TLR2 peptide treatment ameliorated colitis, it allowed recruited monocytes to give rise to macrophages that lack the detrimental proinflammatory gene signature and reduced potentially damaging neutrophil infiltrates. Finally, we demonstrate TLR blocking activity of the peptide on in vitro cultured human monocyte-derived macrophages. Collectively, we provide a significantly improved anti-inflammatory TLR2 peptide and critical insights in its mechanism of action toward future potential use in the clinic.

    更新日期:2020-01-22
  • Characterization of Hagfish (Eptatretus burgeri) Variable Lymphocyte Receptor–Based Antibody and Its Potential Role in the Neutralization of Nervous Necrosis Virus
    J. Immunol. (IF 4.718) Pub Date : 2020-02-01
    Jae Wook Jung; Jung Seok Lee; Jaesung Kim; Se Pyeong Im; Si Won Kim; Jassy Mary S. Lazarte; Young Rim Kim; Jin Hong Chun; Min Woo Ha; Hyeong Su Kim; Kim D. Thompson; Tae Sung Jung

    The variable lymphocyte receptor (VLR) mediates the humoral immune response in jawless vertebrates, including lamprey (Petromyzon marinus) and hagfish (Eptatretus burgeri). Hagfish VLRBs are composed of leucine-rich repeat (LRR) modules, conjugated with a superhydrophobic C-terminal tail, which contributes to low levels of expression in recombinant protein technology. In this study, we screened Ag-specific VLRBs from hagfish immunized with nervous necrosis virus (NNV). The artificially multimerized form of VLRB was constructed using a mammalian expression system. To enhance the level of expression of the Ag-specific VLRB, mutagenesis of the VLRB was achieved in vitro through domain swapping of the LRR C-terminal cap and variable LRR module. The mutant VLRB obtained, with high expression and secretion levels, was able to specifically recognize purified and progeny NNV, and the Ag binding ability of this mutant was increased by at least 250-fold to that of the nonmutant VLRB. Furthermore, preincubation of the Ag-specific VLRB with NNV reduced the infectivity of NNV in E11 cells in vitro, and in vivo experiment. Our results suggest that the newly developed Ag-specific VLRB has the potential to be used as diagnostic and therapeutic reagents for NNV infections in fish.

    更新日期:2020-01-22
  • Pyruvate Kinase M2 Promotes Expression of Proinflammatory Mediators in House Dust Mite–Induced Allergic Airways Disease
    J. Immunol. (IF 4.718) Pub Date : 2020-01-10
    Cheryl van de Wetering; Reem Aboushousha; Allison M. Manuel; Shi B. Chia; Cuixia Erickson; Maximilian B. MacPherson; Jos L. van der velden; Vikas Anathy; Anne E. Dixon; Charles G. Irvin; Matthew E. Poynter; Albert van der Vliet; Emiel F. M. Wouters; Niki L. Reynaert; Yvonne M. W. Janssen-Heininger

    Asthma is a chronic disorder characterized by inflammation, mucus metaplasia, airway remodeling, and hyperresponsiveness. We recently showed that IL-1–induced glycolytic reprogramming contributes to allergic airway disease using a murine house dust mite model. Moreover, levels of pyruvate kinase M2 (PKM2) were increased in this model as well as in nasal epithelial cells from asthmatics as compared with healthy controls. Although the tetramer form of PKM2 converts phosphoenolpyruvate to pyruvate, the dimeric form of PKM2 has alternative, nonglycolysis functions as a transcriptional coactivator to enhance the transcription of several proinflammatory cytokines. In the current study, we examined the impact of PKM2 on the pathogenesis of house dust mite–induced allergic airways disease in C57BL/6NJ mice. We report, in this study, that activation of PKM2, using the small molecule activator, TEPP46, augmented PKM activity in lung tissues and attenuated airway eosinophils, mucus metaplasia, and subepithelial collagen. TEPP46 attenuated IL-1β–mediated airway inflammation and expression of proinflammatory mediators. Exposure to TEPP46 strongly decreased the IL-1β–mediated increases in thymic stromal lymphopoietin (TSLP) and GM-CSF in primary tracheal epithelial cells isolated from C57BL/6NJ mice. We also demonstrate that IL-1β–mediated increases in nuclear phospho-STAT3 were decreased by TEPP46. Finally, STAT3 inhibition attenuated the IL-1β–induced release of TSLP and GM-CSF, suggesting that the ability of PKM2 to phosphorylate STAT3 contributes to its proinflammatory function. Collectively, these results demonstrate that the glycolysis-inactive form of PKM2 plays a crucial role in the pathogenesis of allergic airways disease by increasing IL-1β–induced proinflammatory signaling, in part, through phosphorylation of STAT3.

    更新日期:2020-01-10
  • A 20-Year Journey from Axonal Injury to Neurodegenerative Diseases and the Prospect of Immunotherapy for Combating Alzheimer’s Disease
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    Michal Schwartz; Javier M. Peralta Ramos; Hila Ben-Yehuda

    The understanding of the dialogue between the brain and the immune system has undergone dramatic changes over the last two decades, with immense impact on the perception of neurodegenerative diseases, mental dysfunction, and many other brain pathologic conditions. Accumulated results have suggested that optimal function of the brain is dependent on support from the immune system, provided that this immune response is tightly controlled. Moreover, in contrast to the previous prevailing dogma, it is now widely accepted that circulating immune cells are needed for coping with brain pathologies and that their optimal effect is dependent on their type, location, and activity. In this perspective, we describe our own scientific journey, reviewing the milestones in attaining this understanding of the brain–immune axis integrated with numerous related studies by others. We then explain their significance in demonstrating the possibility of harnessing the immune system in a well-controlled manner for the treatment of neurodegenerative diseases.

    更新日期:2020-01-07
  • Unraveling the Plastic Peripheral Neuroimmune Interactome
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    Aakanksha Jain; Sara Hakim; Clifford J. Woolf

    Sensory neurons and immune cells share a common microenvironmental niche for surveying tissue integrity. The immune and nervous systems both sense deviations in homeostasis and initiate protective responses and, upon malfunction, also jointly contribute to disease. Barrier tissues are heavily innervated by nociceptors, the sensory neurons that detect noxious stimuli, leading to pain and itch. The same tissues are also home to diverse immune cells that respond to infections and injury. The physical proximity of nociceptors and immune cells allows for direct local interactions between the two, independent of the CNS. We discuss in this study their ligand–receptor–based interactions and propose the need to shift from studying individual neuroimmune interactions to exploring the reciprocal neuroimmune interaction network in its entirety: the “neuroimmune interactome.” Identification of the nature of the interactome in health and its plasticity in disease will unravel the functional consequences of interactions between nociceptors and immune cells.

    更新日期:2020-01-07
  • Neuronal Regulation of Cutaneous Immunity
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    Jonathan A. Cohen; Jianing Wu; Daniel H. Kaplan

    The skin is innervated by numerous sensory afferent neurons that respond to a diverse array of stimuli ranging from gentle touch to noxious pain. Various features of the immune system—pathogen recognition, secretion of soluble mediators—are shared with the nervous system. This has led to the recognition that neurons share some functions with innate immune cells and have the capacity to recognize pathogens and participate in innate immune responses. Neuroimmune interactions are bidirectional. Soluble mediators from immune cells activate neurons and soluble mediators from neurons can activate immune cells. In this review, we will focus on the interplay between neurons and innate immunity in the skin in the context of host defense and inflammation.

    更新日期:2020-01-07
  • Origin and Differentiation of Nerve-Associated Macrophages
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    Julia Kolter; Katrin Kierdorf; Philipp Henneke

    The mature peripheral nervous system is a steady network structure yet shows remarkable regenerative properties. The interaction of peripheral nerves with myeloid cells has largely been investigated in the context of damage, following trauma or infection. Recently, specific macrophages dedicated to homeostatic peripheral nerves have come into focus. These macrophages are defined by tissue and nerve type, are seeded in part prenatally, and self-maintain via proliferation. Thus, they are markedly distinct from monocyte-derived macrophages invading after local disturbance of nerve integrity. The phenotypic and transcriptional adaptation of macrophages to the discrete nervous niche may exert axon guidance and nerve regeneration and thus contribute to the stability of the peripheral nervous network. Deciphering these conserved macrophage–nerve interactions offers new translational perspectives for chronic diseases of the peripheral nervous system, such as diabetic neuropathy and pain.

    更新日期:2020-01-07
  • The Neuroimmune Axis in the Tumor Microenvironment
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    Michael R. Shurin; Galina V. Shurin; Samuel B. Zlotnikov; Yuri L. Bunimovich

    Cancer is a complex ecosystem and should be considered in the context of its cellular and molecular microenvironment, which includes the nerves. Peripheral nerves can modulate phenotype and behavior of the malignant cells and thus affect tumor growth and metastasis. Only recently has the role of neuroimmune cross-talk surfaced as a key contributor to cancer progression. However, little is known about the immunomodulatory role of the neuroglial cells in cancer progression and metastasis and the response to therapy. Schwann cells, the principal glial cells of the peripheral nervous system, are now considered to be important players in the tumor microenvironment. They can directly accelerate malignant cell migration and the formation of metastases. Better understanding of the neuroimmune circuits in the tumor milieu will be instrumental in the development of novel therapeutic approaches for the malignancies known to be associated with inflammation and dysregulated immune responses.

    更新日期:2020-01-07
  • Meningeal Lymphatics: From Anatomy to Central Nervous System Immune Surveillance
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    Zachary Papadopoulos; Jasmin Herz; Jonathan Kipnis

    At steady state, the CNS parenchyma has few to no lymphocytes and less potent Ag-presentation capability compared with other organs. However, the meninges surrounding the CNS host diverse populations of immune cells that influence how CNS-related immune responses develop. Interstitial and cerebrospinal fluid produced in the CNS is continuously drained, and recent advances have emphasized that this process is largely taking place through the lymphatic system. To what extent this fluid process mobilizes CNS-derived Ags toward meningeal immune cells and subsequently the peripheral immune system through the lymphatic vessel network is a question of significant clinical importance for autoimmunity, tumor immunology, and infectious disease. Recent advances in understanding the role of meningeal lymphatics as a communicator between the brain and peripheral immunity are discussed in this review.

    更新日期:2020-01-07
  • Brain Parenchymal and Extraparenchymal Macrophages in Development, Homeostasis, and Disease
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    Simone Brioschi; Yingyue Zhou; Marco Colonna

    Microglia are parenchymal macrophages of the CNS; as professional phagocytes they are important for maintenance of the brain’s physiology. These cells are generated through primitive hematopoiesis in the yolk sac and migrate into the brain rudiment after establishment of embryonic circulation. Thereafter, microglia develop in a stepwise fashion, reaching complete maturity after birth. In the CNS, microglia self-renew without input from blood monocytes. Recent RNA-sequencing studies have defined a molecular signature for microglia under homeostasis. However, during disease, microglia undergo remarkable phenotypic changes, which reflect the acquisition of specialized functions tailored to the pathological context. In addition to microglia, the brain-border regions host populations of extraparenchymal macrophages with disparate origins and phenotypes that have recently been delineated. In this review we outline recent findings that provide a deeper understanding of both parenchymal microglia and extraparenchymal brain macrophages in homeostasis and during disease.

    更新日期:2020-01-07
  • Complement-Mediated Events in Alzheimer’s Disease: Mechanisms and Potential Therapeutic Targets
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    Andrea J. Tenner

    An estimated 5.7 million Americans suffer from Alzheimer's disease in the United States, with no disease-modifying treatments to prevent or treat cognitive deficits associated with the disease. Genome-wide association studies suggest that an enhancement of clearance mechanisms and/or promotion of an anti-inflammatory response may slow or prevent disease progression. Increasing awareness of distinct roles of complement components in normal brain development and function and in neurodegenerative disorders align with complement-mediated responses, and thus, thorough understanding of these molecular pathways is needed to facilitate successful therapeutic design. Both beneficial and detrimental effects of C1q as well as contributions to local inflammation by C5a–C5aR1 signaling in brain highlight the need for precision of therapeutic design. The potential benefit of β-amyloid clearance from the circulation via CR1-mediated mechanisms is also reviewed. Therapies that suppress inflammation while preserving protective effects of complement could be tested now to slow the progression of this debilitating disease.

    更新日期:2020-01-07
  • Cytokines and Chemokines in the Pathogenesis of Experimental Autoimmune Encephalomyelitis
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    William J. Karpus

    Experimental autoimmune encephalomyelitis is a CD4+ T cell–mediated demyelinating disease of the CNS that serves as a model for multiple sclerosis. Cytokines and chemokines shape Th1 and Th17 effector responses as well as regulate migration of leukocytes to the CNS during disease. The CNS cellular infiltrate consists of Ag-specific and nonspecific CD4+ and CD8+ T cells, neutrophils, B cells, monocytes, macrophages, and dendritic cells. The mechanism of immune-mediated inflammation in experimental autoimmune encephalomyelitis has been extensively studied in an effort to develop therapeutic modalities for multiple sclerosis and, indeed, has provided insight in modern drug discovery. The present Brief Review highlights critical pathogenic aspects of cytokines and chemokines involved in generation of effector T cell responses and migration of inflammatory cells to the CNS. Select cytokines and chemokines are certainly important in the regulatory response, which involves T regulatory, B regulatory, and myeloid-derived suppressor cells. However, that discussion is beyond the scope of this brief review.

    更新日期:2020-01-07
  • Desperately Seeking Therapies for Cerebral Malaria
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    Brittany A. Riggle; Louis H. Miller; Susan K. Pierce

    Malaria is a deadly infectious disease caused by parasites of the Plasmodium spp. that takes an estimated 435,000 lives each year, primarily among young African children. For most children, malaria is a febrile illness that resolves with time, but in ∼1% of cases, for reasons we do not understand, malaria becomes severe and life threatening. Cerebral malaria (CM) is the most common form of severe malaria, accounting for the vast majority of childhood deaths from malaria despite highly effective antiparasite chemotherapy. Thus, CM is one of the most prevalent lethal brain diseases, and one for which we have no effective therapy. CM is, in part, an immune-mediated disease, and to fully understand CM, it is essential to appreciate the complex relationship between the malarial parasite and the human immune system. In this study, we provide a primer on malaria for immunologists and, in this context, review progress identifying targets for therapeutic intervention.

    更新日期:2020-01-07
  • Self-Antigens Displayed on Liposomal Nanoparticles above a Threshold of Epitope Density Elicit Class-Switched Autoreactive Antibodies Independent of T Cell Help
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    Zhilin Chen; Wei-Yun Wholey; Alireza Hassani Najafabadi; James J. Moon; Irina Grigorova; Bryce Chackerian; Wei Cheng

    Epitope density has a profound impact on B cell responses to particulate Ags, the molecular mechanisms of which remain to be explored. To dissect the role of epitope density in this process, we have synthesized a series of liposomal particles, similar to the size of viruses, that display a model self-antigen peptide at defined surface densities. Immunization of C57BL/6J mice using these particles elicited both IgM and class-switched IgG1, IgG2b, and IgG3 autoreactive Abs that depended on the epitope density. In C57BL/6 gene knockout mice lacking either functional TCRs or MHC class II molecules on B cells, the liposomal particles also elicited IgM, IgG1, IgG2b, and IgG3 responses that were comparable in magnitudes to wild-type mice, suggesting that this B cell response was independent of cognate T cell help. Notably, the titer of the IgG in wild-type animals could be increased by more than 200-fold upon replacement of liposomes with bacteriophage Qβ virus-like particles that displayed the same self-antigen peptide at comparable epitope densities. This enhancement was lost almost completely in gene knockout mice lacking either TCRs or MHC class II molecules on B cells. In conclusion, epitope density above a threshold on particulate Ags can serve as a stand-alone signal to trigger secretion of autoreactive and class-switched IgG in vivo in the absence of cognate T cell help or any adjuvants. The extraordinary immunogenicity of Qβ viral-like particles relies, in large part, on their ability to effectively recruit T cell help after B cell activation.

    更新日期:2020-01-07
  • T Cells Produce IFN-α in the TREX1 D18N Model of Lupus-like Autoimmunity
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    Sean R. Simpson; Stephen L. Rego; Scott E. Harvey; Mingyong Liu; Wayne O. Hemphill; Rajkumar Venkatadri; Rahul Sharma; Jason M. Grayson; Fred W. Perrino

    Autoimmunity can result when cells fail to properly dispose of DNA. Mutations in the three-prime repair exonuclease 1 (TREX1) cause a spectrum of human autoimmune diseases resembling systemic lupus erythematosus. The cytosolic dsDNA sensor, cyclic GMP–AMP synthase (cGAS), and the stimulator of IFN genes (STING) are required for pathogenesis, but specific cells in which DNA sensing and subsequent type I IFN (IFN-I) production occur remain elusive. In this study, we demonstrate that TREX1 D18N catalytic deficiency causes dysregulated IFN-I signaling and autoimmunity in mice. Moreover, we show that bone marrow–derived cells drive this process. We identify both innate immune and, surprisingly, activated T cells as sources of pathological IFN-α production. These findings demonstrate that TREX1 enzymatic activity is crucial to prevent inappropriate DNA sensing and IFN-I production in immune cells, including normally low-level IFN-α–producing cells. These results expand our understanding of DNA sensing and innate immunity in T cells and may have relevance to the pathogenesis of human disease caused by TREX1 mutation.

    更新日期:2020-01-07
  • Overexpression of SH2-Containing Inositol Phosphatase Contributes to Chronic Lymphocytic Leukemia Survival
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    Simar Pal Singh; Marjolein J. W. de Bruijn; Catarina Velaso Gago da Graça; Odilia B. J. Corneth; Jasper Rip; Ralph Stadhouders; Ruud W. J. Meijers; Stéphane Schurmans; William G. Kerr; Johanna ter Burg; Eric Eldering; Anton W. Langerak; Saravanan Y. Pillai; Rudi W. Hendriks

    Balanced activity of kinases and phosphatases downstream of the BCR is essential for B cell differentiation and function and is disturbed in chronic lymphocytic leukemia (CLL). In this study, we employed IgH.TEμ mice, which spontaneously develop CLL, and stable EMC CLL cell lines derived from these mice to explore the role of phosphatases in CLL. Genome-wide expression profiling comparing IgH.TEμ CLL cells with wild-type splenic B cells identified 96 differentially expressed phosphatase genes, including SH2-containing inositol phosphatase (Ship2). We found that B cell–specific deletion of Ship2, but not of its close homolog Ship1, significantly reduced CLL formation in IgH.TEμ mice. Treatment of EMC cell lines with Ship1/2 small molecule inhibitors resulted in the induction of caspase-dependent apoptosis. Using flow cytometry and Western blot analysis, we observed that blocking Ship1/2 abrogated EMC cell survival by exerting dual effects on the BCR signaling cascade. On one hand, specific Ship1 inhibition enhanced calcium signaling and thereby abrogated an anergic response to BCR stimulation in CLL cells. On the other hand, concomitant Ship1/Ship2 inhibition or specific Ship2 inhibition reduced constitutive activation of the mTORC1/ribosomal protein S6 pathway and downregulated constitutive expression of the antiapoptotic protein Mcl-1, in both EMC cell lines and primary IgH.TEμ CLL cells. Importantly, also in human CLL, we found overexpression of many phosphatases including SHIP2. Inhibition of SHIP1/SHIP2 reduced cellular survival and S6 phosphorylation and enhanced basal calcium levels in human CLL cells. Taken together, we provide evidence that SHIP2 contributes to CLL pathogenesis in mouse and human CLL.

    更新日期:2020-01-07
  • A Computationally Optimized Broadly Reactive Antigen Subtype–Specific Influenza Vaccine Strategy Elicits Unique Potent Broadly Neutralizing Antibodies against Hemagglutinin
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    Giuseppe A. Sautto; Greg A. Kirchenbaum; Rodrigo B. Abreu; Jeffrey W. Ecker; Spencer R. Pierce; Harry Kleanthous; Ted M. Ross

    Computationally optimized broadly reactive Ags (COBRA) targeting H1 elicit a broad cross-reactive and cross-neutralizing Ab response against multiple H1N1 viral strains. To assess B cell breadth, Mus musculus (BALB/c) Ab-secreting cells elicited by a candidate COBRA hemagglutinin (HA) (termed P1) were compared with Ab-secreting cells elicited by historical H1N1 vaccine strains. In addition, to evaluate the Ab response elicited by P1 HA at increased resolution, a panel of P1 HA-specific B cell hybridomas was generated following immunization of mice with COBRA P1 and the corresponding purified mAbs were characterized for Ag specificity and neutralization activity. Both head- and stem-directed mAbs were elicited by the P1 HA Ag, with some mAbs endowed with Ab-dependent cell-mediated cytotoxicity activity. P1 HA-elicited mAbs exhibited a wide breadth of HA recognition, ranging from narrowly reactive to broadly reactive mAbs. Interestingly, we identified a P1 HA-elicited mAb (1F8) exhibiting broad hemagglutination inhibition activity against both seasonal and pandemic H1N1 influenza strains. Furthermore, mAb 1F8 recognized an overlapping, but distinct, epitope compared with other narrowly hemagglutination inhibition–positive mAbs elicited by the P1 or wild-type HA Ags. Finally, P1 HA-elicited mAbs were encoded by distinct H chain variable and L chain variable gene segment rearrangements and possessed unique CDR3 sequences. Collectively, the functional characterization of P1 HA-elicited mAbs sheds further insights into the underlying mechanism(s) of expanded Ab breadth elicited by a COBRA HA-based immunogen and advances efforts toward design and implementation of a more broadly protective influenza vaccine.

    更新日期:2020-01-07
  • Borrelia miyamotoi Activates Human Dendritic Cells and Elicits T Cell Responses
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    Lauren M. K. Mason; Joris Koetsveld; Jos J. A. Trentelman; Tanja M. Kaptein; Dieuwertje Hoornstra; Alex Wagemakers; Michelle M. Fikrig; Jasmin I. Ersoz; Anneke Oei; Teunis B. H. Geijtenbeek; Joppe W. R. Hovius

    The spirochete Borrelia miyamotoi has recently been shown to cause relapsing fever. Like the Lyme disease agent, Borrelia burgdorferi, B. miyamotoi is transmitted through the bite of infected ticks; however, little is known about the response of the immune system upon infection. Dendritic cells (DCs) play a central role in the early immune response against B. burgdorferi. We investigated the response of DCs to two different strains of B. miyamotoi using in vitro and ex vivo models and compared this to the response elicited by B. burgdorferi. Our findings show that B. miyamotoi is phagocytosed by monocyte-derived DCs, causing upregulation of activation markers and production of proinflammatory cytokines in a similar manner to B. burgdorferi. Recognition of B. miyamotoi was demonstrated to be partially mediated by TLR2. DCs migrated out of human skin explants upon inoculation of the skin with B. miyamotoi. Finally, we showed that B. miyamotoi–stimulated DCs induced proliferation of naive CD4+ and CD8+ T cells to a larger extent than B. burgdorferi. In conclusion, we show in this study that DCs respond to and mount an immune response against B. miyamotoi that is similar to the response to B. burgdorferi and is able to induce T cell proliferation.

    更新日期:2020-01-07
  • Porcine Reproductive and Respiratory Syndrome Virus Enhances Self-Replication via AP-1–Dependent Induction of SOCS1
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    Xuegang Luo; Xin-xin Chen; Songlin Qiao; Rui Li; Sha Xie; Xinyu Zhou; Ruiguang Deng; En-min Zhou; Gaiping Zhang

    Porcine reproductive and respiratory syndrome virus (PRRSV) has caused tremendous economic losses in the swine industry since its emergence in the late 1980s. PRRSV exploits various strategies to evade immune responses and establish chronic persistent infections. Suppressor of cytokine signaling (SOCS) 1, a member of the SOCS family, is a crucial intracellular negative regulator of innate immunity. In this study, it was shown that SOCS1 can be co-opted by PRRSV to evade host immune responses, facilitating viral replication. It was observed that PRRSV induced SOCS1 production in porcine alveolar macrophages, monkey-derived Marc-145 cells, and porcine-derived CRL2843-CD163 cells. SOCS1 inhibited the expression of IFN-β and IFN-stimulated genes, thereby markedly enhancing PRRSV replication. It was observed that the PRRSV N protein has the ability to upregulate SOCS1 production and that nuclear localization signal–2 (NLS-2) is essential for SOCS1 induction. Moreover, SOCS1 upregulation was dependent on p38/AP-1 and JNK/AP-1 signaling pathways rather than classical type I IFN signaling pathways. In summary, to our knowledge, the findings of this study uncovered the molecular mechanism that underlay SOCS1 induction during PRRSV infection, providing new insights into viral immune evasion and persistent infection.

    更新日期:2020-01-07
  • An Early Neutrophil Recruitment into the Infectious Site Is Critical for Bacterial Lipoprotein Tolerance–Afforded Protection against Microbial Sepsis
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    Wenting Chen; Shuqi Zhao; Michael Ita; Yue Li; Jingjing Ji; Yong Jiang; H. Paul Redmond; Jiang Huai Wang; Jinghua Liu

    Bacterial lipoprotein (BLP)–induced tolerance represents an essential regulatory mechanism during bacterial infection and has been shown to protect against microbial sepsis. This protection is generally attributed to BLP-tolerized monocytes/macrophages characterized by hyporesponsiveness in producing inflammatory cytokines and, simultaneously, an augmented antimicrobial activity. However, the contribution of polymorphonuclear neutrophils (PMNs), another major player in innate immunity against bacterial infection, to BLP tolerance–afforded protection against microbial sepsis has not been identified. In this study, we report that induction of BLP tolerance protected mice against cecal ligation and puncture–induced polymicrobial sepsis, with significantly improved survival. Importantly, BLP tolerization via i.p. injection triggered an early PMN recruitment even before bacterial infection and promoted further PMN influx into the infectious site (i.e., the peritoneal cavity upon cecal ligation and puncture–associated septic challenge). Notably, this early PMN influx was mediated by BLP tolerization–induced PMN chemoattractant CXCL2-formed concentration gradient between the circulation and peritoneal cavity. Critically, blockage of PMN influx with the CXCR2 antagonist SB225002 abolished BLP tolerance–afforded protection and rendered BLP-tolerized mice more vulnerable to microbial infection with impaired bacterial clearance and increased overall mortality. Thus, our results highlight that an early recruitment of PMNs in the infectious site, as an important cellular mechanism, contributes to BLP tolerance–afforded protection against microbial sepsis.

    更新日期:2020-01-07
  • IKIP Negatively Regulates NF-κB Activation and Inflammation through Inhibition of IKKα/β Phosphorylation
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    Haifeng Wu; Hansen Liu; Xueying Zhao; Yi Zheng; Bingyu Liu; Lei Zhang; Chengjiang Gao

    Stringent regulation of the transcription factor NF-κB signaling is essential for the activation of host immune responses and maintaining homeostasis, yet the molecular mechanisms involved in its tight regulation are not completely understood. In this study, we report that IKK-interacting protein (IKIP) negatively regulates NF-κB activation. IKIP interacted with IKKα/β to block its association with NEMO, thereby inhibiting the phosphorylation of IKKα/β and the activation of NF-κB. Upon LPS, TNF-α, and IL-1β stimulation, IKIP-deficient macrophages exhibited more and prolonged IKKα/β phosphorylation, IκB, and p65 phosphorylation and production of NF-κB–responsive genes. Moreover, IKIP-deficient mice were more susceptible to LPS-induced septic shock and dextran sodium sulfate–induced colitis. Our study identifies a previously unrecognized role for IKIP in the negative regulation of NF-κB activation by inhibition of IKKα/β phosphorylation through the disruption of IKK complex formation.

    更新日期:2020-01-07
  • A Mitochondrial Micropeptide Is Required for Activation of the Nlrp3 Inflammasome
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    Ankit Bhatta; Maninjay Atianand; Zhaozhao Jiang; Juliet Crabtree; Juliana Blin; Katherine A. Fitzgerald

    Functional peptides encoded by short open reading frames are emerging as important mediators of fundamental biological processes. In this study, we identified a micropeptide produced from a putative long noncoding RNA (lncRNAs) that is important in controlling innate immunity. By studying lncRNAs in mice macrophages, we identified lncRNA 1810058I24Rik, which was downregulated in both human and murine myeloid cells exposed to LPS as well as other TLR ligands and inflammatory cytokines. Analysis of lncRNA 1810058I24Rik subcellular localization revealed that this transcript was localized in the cytosol, prompting us to evaluate its coding potential. In vitro translation with 35S-labeled methionine resulted in translation of a 47 aa micropeptide. Microscopy and subcellular fractionation studies in macrophages demonstrated endogenous expression of this peptide on the mitochondrion. We thus named this gene mitochondrial micropeptide-47 (Mm47). Crispr–Cas9–mediated deletion of Mm47, as well as small interfering RNA studies in mice primary macrophages, showed that the transcriptional response downstream of TLR4 was intact in cells lacking Mm47. In contrast, Mm47-deficient or knockdown cells were compromised for Nlrp3 inflammasome responses. Activation of Nlrc4 or Aim2 inflammasomes were intact in cells lacking Mm47. This study therefore identifies, to our knowledge, a novel mitochondrial micropeptide Mm47 that is required for the activation of the Nlrp3 inflammasome. This work further highlights the functional activity of short open reading frame–encoded peptides and underscores their importance in innate immunity.

    更新日期:2020-01-07
  • Fibrinogen Is a Specific Trigger for Cytolytic Eosinophil Degranulation
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    Mackenzie E. Coden; Lucas F. Loffredo; Matthew T. Walker; Brian M. Jeong; Kiwon Nam; Bruce S. Bochner; Hiam Abdala-Valencia; Sergejs Berdnikovs

    In inflamed human tissues, we often find intact eosinophilic granules, but not eosinophils themselves. Eosinophils, tissue-dwelling granulocytes with several homeostatic roles, have a surprising association with fibrinogen and tissue remodeling. Fibrinogen is a complex glycoprotein with regulatory roles in hemostasis, tumor development, wound healing, and atherogenesis. Despite its significance, the functional link between eosinophils and fibrinogen is not understood. We tested IL-5–primed mouse bone marrow–derived and human blood–sorted eosinophil activity against FITC-linked fibrinogen substrates. The interactions between these scaffolds and adhering eosinophils were quantified using three-dimensional laser spectral, confocal, and transmission electron microscopy. Eosinophils were labeled with major basic protein (MBP) Ab to visualize granules and assessed by flow cytometry. Both mouse and human eosinophils showed firm adhesion and degraded up to 27 ± 3.1% of the substrate area. This co-occurred with active MBP-positive granule release and the expression of integrin CD11b. Mass spectrometry analysis of fibrinogen proteolytic reactions detected the presence of eosinophil peroxidase, MBP, and fibrin α-, β-, and γ-chains. Eosinophil activity was adhesion dependent, as a blocking Ab against CD11b significantly reduced adhesion, degranulation, and fibrinogenolysis. Although adhered, eosinophils exhibited no proteolytic activity on collagen matrices. Cytolytic degranulation was defined by loss of membrane integrity, cell death, and presence of cell-free granules. From transmission electron microscopy images, we observed only fibrinogen-exposed eosinophils undergoing this process. To our knowledge, this is the first report to show that fibrinogen is a specific trigger for cytolytic eosinophil degranulation with implications in human disease.

    更新日期:2020-01-07
  • PD-1 Expression during Acute Infection Is Repressed through an LSD1–Blimp-1 Axis
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    Alexander P. R. Bally; Dennis K. Neeld; Peiyuan Lu; Parimal Majumder; Yan Tang; Benjamin G. Barwick; Qing Wang; Jeremy M. Boss

    During prolonged exposure to Ags, such as chronic viral infections, sustained TCR signaling can result in T cell exhaustion mediated in part by expression of programmed cell death–1 (PD-1) encoded by the Pdcd1 gene. In this study, dynamic changes in histone H3K4 modifications at the Pdcd1 locus during ex vivo and in vivo activation of CD8 T cells suggested a potential role for the histone H3 lysine 4 demethylase LSD1 in regulating PD-1 expression. CD8 T cells lacking LSD1 expressed higher levels of Pdcd1 mRNA following ex vivo stimulation as well as increased surface levels of PD-1 during acute, but not chronic, infection with lymphocytic choriomeningitis virus (LCMV). Blimp-1, a known repressor of PD-1, recruited LSD1 to the Pdcd1 gene during acute, but not chronic, LCMV infection. Loss of DNA methylation at Pdcd1’s promoter-proximal regulatory regions is highly correlated with its expression. However, following acute LCMV infection, in which PD-1 expression levels return to near baseline, LSD1-deficient CD8 T cells failed to remethylate the Pdcd1 locus to the levels of wild-type cells. Finally, in a murine melanoma model, the frequency of PD-1–expressing tumor-infiltrating LSD1-deficient CD8 T cells was greater than in wild type. Thus, LSD1 is recruited to the Pdcd1 locus by Blimp-1, downregulates PD-1 expression by facilitating the removal of activating histone marks, and is important for remethylation of the locus. Together, these data provide insight into the complex regulatory mechanisms governing T cell immunity and regulation of a critical T cell checkpoint gene.

    更新日期:2020-01-07
  • Elevated Choline Kinase α–Mediated Choline Metabolism Supports the Prolonged Survival of TRAF3-Deficient B Lymphocytes
    J. Immunol. (IF 4.718) Pub Date : 2020-01-15
    Samantha Gokhale; Wenyun Lu; Sining Zhu; Yingying Liu; Ronald P. Hart; Joshua D. Rabinowitz; Ping Xie

    Specific deletion of the tumor suppressor TRAF3 from B lymphocytes in mice leads to the prolonged survival of mature B cells and expanded B cell compartments in secondary lymphoid organs. In the current study, we investigated the metabolic basis of TRAF3-mediated regulation of B cell survival by employing metabolomic, lipidomic, and transcriptomic analyses. We compared the polar metabolites, lipids, and metabolic enzymes of resting splenic B cells purified from young adult B cell–specific Traf3−/− and littermate control mice. We found that multiple metabolites, lipids, and enzymes regulated by TRAF3 in B cells are clustered in the choline metabolic pathway. Using stable isotope labeling, we demonstrated that phosphocholine and phosphatidylcholine biosynthesis was markedly elevated in Traf3−/− mouse B cells and decreased in TRAF3-reconstituted human multiple myeloma cells. Furthermore, pharmacological inhibition of choline kinase α, an enzyme that catalyzes phosphocholine synthesis and was strikingly increased in Traf3−/− B cells, substantially reversed the survival phenotype of Traf3−/− B cells both in vitro and in vivo. Taken together, our results indicate that enhanced phosphocholine and phosphatidylcholine synthesis supports the prolonged survival of Traf3−/− B lymphocytes. Our findings suggest that TRAF3-regulated choline metabolism has diagnostic and therapeutic value for B cell malignancies with TRAF3 deletions or relevant mutations.

    更新日期:2020-01-07
  • Allergin-1 Immunoreceptor Suppresses House Dust Mite–Induced Allergic Airway Inflammation
    J. Immunol. (IF 4.718) Pub Date : 2020-01-03
    Haruka Miki; Satoko Tahara-Hanaoka; Mariana Silva Almeida; Kaori Hitomi; Shohei Shibagaki; Kazumasa Kanemaru; Yu-Hsien Lin; Kanako Iwata; Shota Miyake; Shiro Shibayama; Takayuki Sumida; Kazuko Shibuya; Akira Shibuya

    House dust mite (HDM) allergens are leading causes of allergic asthma characterized by Th2 responses. The lung-resident CD11b+ dendritic cells (DCs) play a key role in Th2 cell development in HDM-induced allergic asthma. However, the regulatory mechanism of HDM-induced CD11b+ DC activation remains incompletely understood. In this study, we demonstrate that mice deficient in an inhibitory immunoreceptor, Allergin-1, showed exacerbated HDM-induced airway eosinophilia and serum IgE elevation. By using bone marrow–chimeric mice that were sensitized with adoptively transferred HDM-stimulated wild-type or Allergin-1–deficient CD11b+ bone marrow–derived cultured DCs (BMDCs), followed by challenge with HDM, we show that Allergin-1 on the BMDCs suppressed HDM-induced allergic airway inflammation. We also show that Allergin-1 suppressed HDM-induced PGE2 production from CD11b+ BMDCs by inhibiting Syk tyrosine kinase activation through recruitment of SHP-1, subsequently leading to negative regulation of Th2 responses. These results suggest that Allergin-1 plays an important role in regulation of HDM-induced allergic airway inflammation.

    更新日期:2020-01-04
  • Immunodominant AH1 Antigen-Deficient Necroptotic, but Not Apoptotic, Murine Cancer Cells Induce Antitumor Protection
    J. Immunol. (IF 4.718) Pub Date : 2020-01-03
    Tania Løve Aaes; Hanne Verschuere; Agnieszka Kaczmarek; Liesbeth Heyndrickx; Bartosz Wiernicki; Iris Delrue; Bram De Craene; Joachim Taminau; Tinneke Delvaeye; Mathieu J. M. Bertrand; Wim Declercq; Geert Berx; Dmitri V. Krysko; Sandy Adjemian; Peter Vandenabeele

    Immunogenic cell death (ICD) occurs when a dying cell releases cytokines and damage-associated molecular patterns, acting as adjuvants, and expresses Ags that induce a specific antitumor immune response. ICD is studied mainly in the context of regulated cell death pathways, especially caspase-mediated apoptosis marked by endoplasmic reticulum stress and calreticulin exposure and, more recently, also in relation to receptor-interacting protein kinase–driven necroptosis, whereas unregulated cell death like accidental necrosis is nonimmunogenic. Importantly, the murine cancer cell lines used in ICD studies often express virally derived peptides that are recognized by the immune system as tumor-associated Ags. However, it is unknown how different cell death pathways may affect neoepitope cross-presentation and Ag recognition of cancer cells. We used a prophylactic tumor vaccination model and observed that both apoptotic and necroptotic colon carcinoma CT26 cells efficiently immunized mice against challenge with a breast cancer cell line that expresses the same immunodominant tumor Ag, AH1, but only necroptotic CT26 cells would mount an immune response against CT26-specific neoepitopes. By CRISPR/Cas9 genome editing, we knocked out AH1 and saw that only necroptotic CT26 cells were still able to protect mice against tumor challenge. Hence, in this study, we show that endogenous AH1 tumor Ag expression can mask the strength of immunogenicity induced by different cell death pathways and that upon knockout of AH1, necroptosis was more immunogenic than apoptosis in a prophylactic tumor vaccination model. This work highlights necroptosis as a possible preferred ICD form over apoptosis in the treatment of cancer.

    更新日期:2020-01-04
  • Neonatal Injury Increases Gut Permeability by Epigenetically Suppressing E-Cadherin in Adulthood
    J. Immunol. (IF 4.718) Pub Date : 2019-12-30
    Kevin T. Kline; Haifeng Lian; Xiaoying S. Zhong; Xiuju Luo; John H. Winston; Yingzi Cong; Tor C. Savidge; Roderick H. Dashwood; Don W. Powell; Qingjie Li

    Altered intestinal epithelial integrity is an important susceptibility trait in inflammatory bowel disease (IBD), and early life stressors are reported to contribute to this disease susceptibility in adulthood. To identify disease mechanisms associated with early-life trauma that exacerbate IBD in adulthood, we used a “double-hit” neonatal inflammation (NI) and adult inflammation (AI) model that exhibits more severe mucosal injury in the colon later in life. In this study, we explore the underlying mechanisms of this aggravated injury. In rats exposed to both NI and AI, we found sustained increases in colonic permeability accompanied by significantly attenuated expression of the epithelial junction protein E-cadherin. Quantitative RT-PCR revealed a decreased Cdh1 (gene of E-cadherin) mRNA expression in NI + AI rats compared with NI or AI rats. Next, we performed microRNA microarrays to identify potential regulators of E-cadherin in NI + AI rats. We confirmed the overexpression of miR-155, a predicted regulator of E-cadherin, and selected it for further analysis based on reported significance in human IBD. Using ingenuity pathway analysis software, the targets and related canonical pathway of miR-155 were analyzed. Mechanistic studies identified histone hyperacetylation at the Mir155 promoter in NI + AI rats, concomitant with elevated RNA polymerase II binding. In vitro, E-cadherin knockdown markedly increased epithelial cell permeability, as did overexpression of miR-155 mimics, which significantly suppressed E-cadherin protein. In vivo, NI + AI colonic permeability was significantly reversed with administration of miR-155 inhibitor rectally. Our collective findings indicate that early-life inflammatory stressors trigger a significant and sustained epithelial injury by suppressing E-cadherin through epigenetic mechanisms.

    更新日期:2019-12-30
  • CD13/Aminopeptidase N Is a Potential Therapeutic Target for Inflammatory Disorders
    J. Immunol. (IF 4.718) Pub Date : 2020-01-01
    Chenyang Lu; Mohammad A. Amin; David A. Fox

    CD13/aminopeptidase N is a widely expressed ectoenzyme with multiple functions. As an enzyme, CD13 regulates activities of numerous cytokines by cleaving their N-terminals and is involved in Ag processing by trimming the peptides bound to MHC class II. Independent of its enzymatic activity, cell membrane CD13 functions by cross-linking–induced signal transduction, regulation of receptor recycling, enhancement of FcγR-mediated phagocytosis, and acting as a receptor for cytokines. Moreover, soluble CD13 has multiple proinflammatory roles mediated by binding to G-protein–coupled receptors. CD13 not only modulates development and activities of immune-related cells, but also regulates functions of inflammatory mediators. Therefore, CD13 is important in the pathogenesis of various inflammatory disorders. Inhibitors of CD13 have shown impressive anti-inflammatory effects, but none of them has yet been used for clinical therapy of human inflammatory diseases. We reevaluate CD13’s regulatory role in inflammation and suggest that CD13 could be a potential therapeutic target for inflammatory disorders.

    更新日期:2019-12-18
  • AID Phosphorylation Regulates Mismatch Repair–Dependent Class Switch Recombination and Affinity Maturation
    J. Immunol. (IF 4.718) Pub Date : 2020-01-01
    Jee Eun Choi; Allysia J. Matthews; Genesis Michel; Bao Q. Vuong

    Activation-induced cytidine deaminase (AID) generates U:G mismatches in Ig genes that can be converted into untemplated mutations during somatic hypermutation or DNA double-strand breaks during class switch recombination (CSR). Null mutations in UNG and MSH2 demonstrate the complementary roles of the base excision repair (BER) and mismatch repair pathways, respectively, in CSR. Phosphorylation of AID at serine 38 was previously hypothesized to regulate BER during CSR, as the AID phosphorylation mutant, AID(S38A), cannot interact with APE1, a BER protein. Consistent with these findings, we observe a complete block in CSR in AIDS38A/S38AMSH2−/− mouse B cells that correlates with an impaired mutation frequency at 5′Sμ. Similarly, somatic hypermutation is almost negligible at the JH4 intron in AIDS38A/S38AMSH2−/− mouse B cells, and, consistent with this, NP-specific affinity maturation in AIDS38A/S38AMSH2−/− mice is not significantly elevated in response to NP-CGG immunization. Surprisingly, AIDS38A/S38AUNG−/− mouse B cells also cannot complete CSR or affinity maturation despite accumulating significant mutations in 5′Sμ as well as the JH4 intron. These data identify a novel role for phosphorylation of AID at serine 38 in mismatch repair–dependent CSR and affinity maturation.

    更新日期:2019-12-18
  • Foliate Lymphoid Aggregates as Novel Forms of Serous Lymphocyte Entry Sites of Peritoneal B Cells and High-Grade B Cell Lymphomas
    J. Immunol. (IF 4.718) Pub Date : 2020-01-01
    Xinkai Jia; Fanni Gábris; Óli Jacobsen; Gábor Bedics; Bálint Botz; Zsuzsanna Helyes; Zoltán Kellermayer; Dóra Vojkovics; Gergely Berta; Nándor Nagy; Zoltán Jakus; Péter Balogh

    The cellular homeostasis of lymphoid tissues is determined by the continuous interactions of mobile hematopoietic cells within specialized microenvironments created by sessile stromal cells. In contrast to the lymph nodes and mucosal lymphoid tissues with well-defined entry and exit routes, the movement of leukocytes in the peritoneal cavity is largely unknown. In this study, we report that, in addition to the omental milky spots and fat-associated lymphoid clusters, in mice, the serous surface of the mesenteric adipose streaks contains lymphocyte-rich organoids comprised of a highly compacted leaf-like part connected to the adipose tissue that can also efficiently bind B cells and high-grade B cell lymphoma (diffuse large B cell lymphoma) cells. Denoted as foliate lymphoid aggregates (FLAgs), these structures show incomplete T/B segregation and a partially differentiated stromal architecture. LYVE-1–positive macrophages covering FLAgs efficiently bind i.p. injected normal B cells as well as different types of diffuse large B cell lymphoma cells. Within FLAgs, the lymphocytes compartmentalize according to their chemokine receptor pattern and subsequently migrate toward the mesenteric lymph nodes via the mesenteric lymphatic capillaries. The blood supply of FLAgs includes short vascular segments displaying peripheral lymph node addressin, and the extravasation of lymphocytes to the omental and mesenteric adipose tissues is partly mediated by L-selectin. The appearance of i.p. injected cells in mesenteric lymph nodes suggests that the mesentery-associated lymphatics may also collect leukocytes from the fat-associated lymphoid clusters and FLAgs, thus combining the mucosal and serous exit of mobile leukocytes and increasing the range of drainage sites for the peritoneal expansion of lymphoid malignancies.

    更新日期:2019-12-18
  • Th1 Cells Rolling on Selectins Trigger DAP12-Dependent Signals That Activate Integrin αLβ2
    J. Immunol. (IF 4.718) Pub Date : 2020-01-01
    Bojing Shao; Tadayuki Yago; Sumith R. Panicker; Nan Zhang; Zhenghui Liu; Rodger P. McEver

    During inflammation, both neutrophils and effector T cells use selectins to roll and integrins to arrest in postcapillary venules. In both cell types, chemokines can transduce signals that convert integrin αLβ2 to a high-affinity conformation, which interacts with ICAM-1 to mediate arrest. In neutrophils, selectins also trigger an immunoreceptor-like signaling cascade that converts integrin αLβ2 to an intermediate-affinity conformation, which interacts with ICAM-1 to slow rolling. It is not known whether selectins induce similar signaling events in T cells. Ag engagement causes phosphorylation of ITAMs on the TCR; these motifs recruit kinases and adaptors that lead to the activation of αLβ2. We found that mouse Th1 cells rolling on P- or E-selectin triggered signals that promoted αLβ2-dependent slow rolling on ICAM-1 in vitro and in vivo. The selectin signaling cascade resembled that used by the TCR, except that unexpectedly, Th1 cells employed the ITAM-bearing protein DAP12, which was not known to be expressed in these cells. Importantly, outside-in signaling through ligand-occupied αLβ2 also required DAP12. Cooperative selectin and chemokine signaling in Th1 cells promoted αLβ2-dependent slow rolling and arrest in vitro and in vivo and migration into Ag-challenged tissues in vivo. Our findings reveal an important function for DAP12 in Th1 cells and a new mechanism to recruit effector T cells to sites of inflammation.

    更新日期:2019-12-18
  • DOCK2 Sets the Threshold for Entry into the Virtual Memory CD8+ T Cell Compartment by Negatively Regulating Tonic TCR Triggering
    J. Immunol. (IF 4.718) Pub Date : 2020-01-01
    Vinay S. Mahajan; Ezana Demissie; Faisal Alsufyani; Sudha Kumari; Grace J. Yuen; Vinayak Viswanadham; Andrew Huang; Johnson Q. Tran; James J. Moon; Darrell J. Irvine; Shiv Pillai

    The control of cytoskeletal dynamics by dedicator of cytokinesis 2 (DOCK2), a hematopoietic cell–specific actin effector protein, has been implicated in TCR signaling and T cell migration. Biallelic mutations in Dock2 have been identified in patients with a recessive form of combined immunodeficiency with defects in T, B, and NK cell activation. Surprisingly, we show in this study that certain immune functions of CD8+ T cells are enhanced in the absence of DOCK2. Dock2-deficient mice have a pronounced expansion of their memory T cell compartment. Bone marrow chimera and adoptive transfer studies indicate that these memory T cells develop in a cell-intrinsic manner following thymic egress. Transcriptional profiling, TCR repertoire analyses, and cell surface marker expression indicate that Dock2-deficient naive CD8+ T cells directly convert into virtual memory cells without clonal effector T cell expansion. This direct conversion to memory is associated with a selective increase in TCR sensitivity to self-peptide MHC in vivo and an enhanced response to weak agonist peptides ex vivo. In contrast, the response to strong agonist peptides remains unaltered in Dock2-deficient T cells. Collectively, these findings suggest that the regulation of the actin dynamics by DOCK2 enhances the threshold for entry into the virtual memory compartment by negatively regulating tonic TCR triggering in response to weak agonists.

    更新日期:2019-12-18
  • The Tetraspanin CD53 Regulates Early B Cell Development by Promoting IL-7R Signaling
    J. Immunol. (IF 4.718) Pub Date : 2020-01-01
    Zev J. Greenberg; Darlene A. Monlish; Rachel L. Bartnett; Yihu Yang; Guomin Shen; Weikai Li; Jeffrey J. Bednarski; Laura G. Schuettpelz

    The tetraspanin CD53 has been implicated in B cell development and function. CD53 is a transcriptional target of EBF1, a critical transcription factor for early B cell development. Further, human deficiency of CD53 results in recurrent infections and reduced serum Igs. Although prior studies have indicated a role for CD53 in regulating mature B cells, its role in early B cell development is not well understood. In this study, we show that CD53 expression, which is minimal on hematopoietic stem and progenitor cells, increases throughout bone marrow B cell maturation, and mice lacking CD53 have significantly decreased bone marrow, splenic, lymphatic, and peripheral B cells. Mixed bone marrow chimeras show that CD53 functions cell autonomously to promote B lymphopoiesis. Cd53−/− mice have reduced surface expression of IL-7Rα and diminished phosphatidylinositol 3 kinase and JAK/STAT signaling in prepro- and pro-B cells. Signaling through these pathways via IL-7R is essential for early B cell survival and transition from the pro-B to pre-B cell developmental stage. Indeed, we find increased apoptosis in developing B cells and an associated reduction in pre-B and immature B cell populations in the absence of CD53. Coimmunoprecipitation and proximity ligation studies demonstrate physical interaction between CD53 and IL-7R. Together, these data, to our knowledge, suggest a novel role for CD53 during IL-7 signaling to promote early B cell differentiation.

    更新日期:2019-12-18
  • Extremely Preterm Infants Have Significant Alterations in Their Conventional T Cell Compartment during the First Weeks of Life
    J. Immunol. (IF 4.718) Pub Date : 2020-01-01
    Khaleda Rahman Qazi; Georg Bach Jensen; Marieke van der Heiden; Sophia Björkander; Ulrika Holmlund; Yeneneh Haileselassie; Efthymia Kokkinou; Giovanna Marchini; Maria C. Jenmalm; Thomas Abrahamsson; Eva Sverremark-Ekström

    Extremely preterm neonates are particularly susceptible to infections, likely because of severely impaired immune function. However, little is known on the composition of the T cell compartment in early life in this vulnerable population. We conducted a comprehensive phenotypic flow cytometry–based longitudinal analysis of the peripheral conventional T cell compartment of human extremely low gestational age neonates (ELGAN) with extremely low birth weight (ELBW; <1000 g) participating in a randomized placebo-controlled study of probiotic supplementation. PBMCs from ELGAN/ELBW neonates were collected at day 14, day 28, and postmenstrual week 36. Comparisons were made with full-term 14-d-old neonates. Total CD4+ and CD8+ T cell frequencies were markedly lower in the preterm neonates. The reduction was more pronounced among the CD8+ population, resulting in an increased CD4/CD8 ratio. The preterm infants were also more Th2 skewed than the full-term infants. Although the frequency of regulatory T cells seemed normal in the ELGAN/ELBW preterm neonates, their expression of the homing receptors α4β7, CCR4, and CCR9 was altered. Notably, ELGAN/ELBW infants developing necrotizing enterocolitis before day 14 had higher expression of CCR9 in CD4+T cells at day 14. Chorioamnionitis clearly associated with reduced T regulatory cell frequencies and functional characteristics within the preterm group. Finally, probiotic supplementation with Lactobacillus reuteri did not impose any phenotypic changes of the conventional T cell compartment. In conclusion, notable immaturities of the T cell compartment in ELGAN/ELBW neonates may at least partially explain their increased susceptibility to severe immune-mediated morbidities.

    更新日期:2019-12-18
  • Two Successive Inversional Vβ Rearrangements on a Single Tcrb Allele Can Contribute to the TCRβ Repertoire
    J. Immunol. (IF 4.718) Pub Date : 2020-01-01
    Kyutae D. Lee; Craig H. Bassing

    Mammalian TCRβ loci contain 30 Vβ gene segments upstream and in the same transcriptional orientation as two DJCβ clusters, and a downstream Vβ (TRBV31) in the opposite orientation. The textbook view is upstream Vβs rearrange only by deletion and TRBV31 rearranges only by inversion to create VβDJCβ genes. In this study, we show in mice that upstream Vβs recombine through inversion to the DJCβ2 cluster on alleles carrying a preassembled Trbv31-DJCβ1 gene. When this gene is in-frame, Trbv5 evades TCRβ-signaled feedback inhibition and recombines by inversion to the DJCβ2 cluster, creating αβ T cells that express assembled Trbv5-DJCβ2 genes. On alleles with an out-of-frame Trbv31-DJCβ1 gene, most upstream Vβs recombine at low levels and promote αβ T cell development, albeit with preferential expansion of Trbv1-DJβ2 rearrangements. Finally, we show wild-type Tcrb alleles produce mature αβ T cells that express upstream Vβ peptides in surface TCRs and carry Trbv31-DJβ2 rearrangements. Our study indicates two successive inversional Vβ-to-DJβ rearrangements on the same allele can contribute to the TCRβ repertoire.

    更新日期:2019-12-18
  • Splenic Red Pulp Macrophages Cross-Prime Early Effector CTL That Provide Rapid Defense against Viral Infections
    J. Immunol. (IF 4.718) Pub Date : 2020-01-01
    Marika Enders; Lars Franken; Marie-Sophie Philipp; Nina Kessler; Ann-Kathrin Baumgart; Melanie Eichler; Emmanuel J. H. Wiertz; Natalio Garbi; Christian Kurts

    Cross-presentation allows dendritic cells (DCs) to present peptides derived from endocytosed Ags on MHC class I molecules, which is important for activating CTL against viral infections and tumors. Type 1 classical DCs (cDC1), which depend on the transcription factor Batf3, are considered the main cross-presenting cells. In this study, we report that soluble Ags are efficiently cross-presented also by transcription factor SpiC-dependent red pulp macrophages (RPM) of the spleen. In contrast to cDC1, RPM used the mannose receptor for Ag uptake and employed the proteasome- and TAP-dependent cytosolic cross-presentation pathway, previously shown to be used in vitro by bone marrow–derived DCs. In an in vivo vaccination model, both cDC1 and RPM cross-primed CTL efficiently but with distinct kinetics. Within a few days, RPM induced very early effector CTL of a distinct phenotype (Ly6A/E+ Ly6C(+) KLRG1− CD127− CX3CR1− Grz-B+). In an adenoviral infection model, such CTL contained the early viral spread, whereas cDC1 induced short-lived effector CTL that eventually cleared the virus. RPM-induced early effector CTL also contributed to the endogenous antiviral response but not to CTL memory generation. In conclusion, RPM can contribute to antiviral immunity by generating a rapid CTL defense force that contains the virus until cDC1-induced CTL are available to eliminate it. This function can be harnessed for improving vaccination strategies aimed at inducing CTL.

    更新日期:2019-12-18
  • Pneumolysin Induces 12-Lipoxygenase–Dependent Neutrophil Migration during Streptococcus pneumoniae Infection
    J. Immunol. (IF 4.718) Pub Date : 2020-01-01
    Walter Adams; Rudra Bhowmick; Elsa N. Bou Ghanem; Kristin Wade; Mikhail Shchepetov; Jeffrey N. Weiser; Beth A. McCormick; Rodney K. Tweten; John M. Leong

    Streptococcus pneumoniae is a major cause of pneumonia, wherein infection of respiratory mucosa drives a robust influx of neutrophils. We have previously shown that S. pneumoniae infection of the respiratory epithelium induces the production of the 12-lipoxygenase (12-LOX)–dependent lipid inflammatory mediator hepoxilin A3, which promotes recruitment of neutrophils into the airways, tissue damage, and lethal septicemia. Pneumolysin (PLY), a member of the cholesterol-dependent cytolysin (CDC) family, is a major S. pneumoniae virulence factor that generates ∼25-nm diameter pores in eukaryotic membranes and promotes acute inflammation, tissue damage, and bacteremia. We show that a PLY-deficient S. pneumoniae mutant was impaired in triggering human neutrophil transepithelial migration in vitro. Ectopic production of PLY endowed the nonpathogenic Bacillus subtilis with the ability to trigger neutrophil recruitment across human-cultured monolayers. Purified PLY, several other CDC family members, and the α-toxin of Clostridium septicum, which generates pores with cross-sectional areas nearly 300 times smaller than CDCs, reproduced this robust neutrophil transmigration. PLY non–pore-forming point mutants that are trapped at various stages of pore assembly did not recruit neutrophils. PLY triggered neutrophil recruitment in a 12-LOX–dependent manner in vitro. Instillation of wild-type PLY but not inactive derivatives into the lungs of mice induced robust 12-LOX–dependent neutrophil migration into the airways, although residual inflammation induced by PLY in 12-LOX–deficient mice indicates that 12-LOX–independent pathways also contribute to PLY-triggered pulmonary inflammation. These data indicate that PLY is an important factor in promoting hepoxilin A3–dependent neutrophil recruitment across pulmonary epithelium in a pore-dependent fashion.

    更新日期:2019-12-18
  • Stochastic Expansions Maintain the Clonal Stability of CD8+ T Cell Populations Undergoing Memory Inflation Driven by Murine Cytomegalovirus
    J. Immunol. (IF 4.718) Pub Date : 2020-01-01
    Corinne J. Smith; Vanessa Venturi; Maire F. Quigley; Holly Turula; Emma Gostick; Kristin Ladell; Brenna J. Hill; Danielle Himelfarb; Kylie M. Quinn; Hui Yee Greenaway; Thurston H. Y. Dang; Robert A. Seder; Daniel C. Douek; Ann B. Hill; Miles P. Davenport; David A. Price; Christopher M. Snyder

    CMV is an obligate and persistent intracellular pathogen that continually drives the production of highly differentiated virus-specific CD8+ T cells in an Ag-dependent manner, a phenomenon known as memory inflation. Extensive proliferation is required to generate and maintain inflationary CD8+ T cell populations, which are counterintuitively short-lived and typically exposed to limited amounts of Ag during the chronic phase of infection. An apparent discrepancy therefore exists between the magnitude of expansion and the requirement for ongoing immunogenic stimulation. To address this issue, we explored the clonal dynamics of memory inflation. First, we tracked congenically marked OT-I cell populations in recipient mice infected with murine CMV (MCMV) expressing the cognate Ag OVA. Irrespective of numerical dominance, stochastic expansions were observed in each population, such that dominant and subdominant OT-I cells were maintained at stable frequencies over time. Second, we characterized endogenous CD8+ T cell populations specific for two classic inflationary epitopes, M38 and IE3. Multiple clonotypes simultaneously underwent Ag-driven proliferation during latent infection with MCMV. In addition, the corresponding CD8+ T cell repertoires were stable over time and dominated by persistent clonotypes, many of which also occurred in more than one mouse. Collectively, these data suggest that stochastic encounters with Ag occur frequently enough to maintain oligoclonal populations of inflationary CD8+ T cells, despite intrinsic constraints on epitope display at individual sites of infection with MCMV.

    更新日期:2019-12-18
  • Platelets Modulate IFN-γ Production against Candida albicans in Peripheral Blood Mononuclear Cells via Prostaglandins
    J. Immunol. (IF 4.718) Pub Date : 2020-01-01
    Intan M. W. Dewi; Floor E. Aleva; Vesla I. Kullaya; Fadel M. Garishah; Quirijn de Mast; André J. A. M. van der Ven; Frank L. van de Veerdonk

    Platelets are known to have immunomodulatory properties. They modulate immune responses of leukocytes against various pathogens, including fungi. Candida albicans can cause systemic infection in immunocompromised individuals that is associated with a high mortality and morbidity. In the current study, we explored the role of platelets in antifungal host defense against C. albicans. PBMCs were stimulated with heat-killed (HK) C. albicans in the presence or absence of isolated washed platelets. Cytokines were quantified from culture supernatants by ELISA. Inhibition of platelet receptors and cytokine pathways were used to elucidate the mechanisms involved in platelet–leukocyte interaction. In the presence of platelets, PBMCs produced less IFN-γ upon stimulation with HK C. albicans. This effect was dependent on the direct contact between platelets and leukocytes but was independent of the platelet GPIb and P-selectin receptors. The attenuation of IFN-γ was not a direct effect on T cells but was dependent on the presence of APC and T cells. Platelets did not modulate the Th-1–polarizing cytokines IL-12 and IL-18. The addition of PG (PGE2) further diminished IFN-γ levels in PBMCs, and supplementation of cells with nonsteroidal anti-inflammatory drugs was able to restore the level of IFN-γ. Overall, we show that modulation of the Th1 response against C. albicans by platelets is dependent on PGs.

    更新日期:2019-12-18
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