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  • Vaccine protection against murid herpesvirus-4 is maintained when the priming virus lacks known latency genes.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-10-21
    Clara Lawler,João Pedro Simas,Philip G Stevenson

    γ-Herpesviruses establish latent infections of lymphocytes and drive their proliferation, causing cancers and motivating a search for vaccines. Effective vaccination against murid herpesvirus-4 (MuHV-4)-driven lymphoproliferation by latency-impaired mutant viruses suggests that lytic access to the latency reservoir is a viable target for control. However, the vaccines retained the immunogenic MuHV-4 M2 latency gene. Here, a strong reduction in challenge virus load was maintained when the challenge virus lacked the main latency-associated CD8+ T-cell epitope of M2, or when the vaccine virus lacked M2 entirely. This protection was maintained also when the vaccine virus lacked both episome maintenance and the genomic region encompassing M1, M2, M3, M4 and ORF4. Therefore, protection did not require immunity to known MuHV-4 latency genes. As the remaining vaccine virus genes have clear homologs in human γ-herpesviruses, this approach of deleting viral latency genes could also be applied to them, to generate safe and effective vaccines against human disease.

    更新日期:2019-11-01
  • Characterization of the γδ T-cell compartment during infancy reveals clear differences between the early neonatal period and 2 years of age.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-11-05
    Marieke van der Heiden,Sophia Björkander,Khaleda Rahman Qazi,Julia Bittmann,Lena Hell,Maria C Jenmalm,Giovanna Marchini,David Vermijlen,Thomas Abrahamsson,Caroline Nilsson,Eva Sverremark-Ekström

    γδ T cells are unconventional T cells that function on the border of innate and adaptive immunity. They are suggested to play important roles in neonatal and infant immunity, although their phenotype and function are not fully characterized in early childhood. We aimed to investigate γδ T cells in relation to age, prematurity and cytomegalovirus (CMV) infection. Therefore, we used flow cytometry to characterize the γδ T-cell compartment in cord blood and peripheral blood cells from 14-day-, 2-year- and 5-year-old children, as well as in peripheral blood samples collected at several time points during the first months of life from extremely premature neonates. γδ T cells were phenotypically similar at 2 and 5 years of age, whereas cord blood was divergent and showed close proximity to γδ T cells from 14-day-old neonates. Interestingly, 2-year-old children and adults showed comparable Vδ2+ γδ T-cell functionality toward both microbial and polyclonal stimulations. Importantly, extreme preterm birth compromised the frequencies of Vδ1+ cells and affected the functionality of Vδ2+ γδ T cells shortly after birth. In addition, CMV infection was associated with terminal differentiation of the Vδ1+ compartment at 2 years of age. Our results show an adult-like functionality of the γδ T-cell compartment already at 2 years of age. In addition, we demonstrate an altered γδ T-cell phenotype early after birth in extremely premature neonates, something which could possible contribute to the enhanced risk for infections in this vulnerable group of children.

    更新日期:2019-11-01
  • Serum IgA Fc effector functions in infectious disease and cancer.
    Immunol. Cell Biol. (IF 3.947) Pub Date : null
    Samantha K Davis,Kevin J Selva,Stephen J Kent,Amy W Chung

    Immunoglobulin A (IgA) is the most abundant antibody isotype present at mucosal surfaces and the second most abundant in human serum. In addition to preventing pathogen entry at mucosal surfaces, IgA can control and eradicate bacterial and viral infections through a variety of antibody-mediated innate effector cell mechanisms. The role of mucosal IgA in infection (e.g. neutralisation) and in inflammatory homeostasis (e.g. allergy and autoimmunity) has been extensively investigated, in contrast serum IgA is comparatively understudied. IgA binding to Fc alpha receptor plays a dual role in the activation and inhibition of innate effector cell functions. Mounting evidence suggests serum IgA induces potent effector functions against various bacterial and some viral infections including Neisseria meningitidis and rotavirus. Furthermore, in the era of immunotherapy, serum IgA provides an interesting alternative to classical IgG monoclonal antibodies to treat cancer and infectious pathogens. Here we discuss the role of serum IgA in infectious diseases with reference to bacterial and viral infections and the potential for IgA as a monoclonal antibody therapy.

    更新日期:2019-11-01
  • Chronically stimulated human MAIT cells are unexpectedly potent IL-13 producers.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-07-20
    Jason Kelly,Yosuke Minoda,Tobias Meredith,Garth Cameron,Marie-Sophie Philipp,Daniel G Pellicci,Alexandra J Corbett,Christian Kurts,Daniel Hd Gray,Dale I Godfrey,George Kannourakis,Stuart P Berzins

    Mucosal-associated invariant T (MAIT) cells are unconventional T cells that recognize antigens derived from riboflavin biosynthesis. In addition to anti-microbial functions, human MAIT cells are associated with cancers, autoimmunity, allergies and inflammatory disorders, although their role is poorly understood. Activated MAIT cells are well known for their rapid release of Th1 and Th17 cytokines, but we have discovered that chronic stimulation can also lead to potent interleukin (IL)-13 expression. We used RNA-seq and qRT-PCR to demonstrate high expression of the IL-13 gene in chronically stimulated MAIT cells, and directly identify IL-13 using intracellular flow cytometry and multiplex bead analysis of MAIT cell cultures. This unexpected finding has important implications for IL-13-dependent diseases, such as colorectal cancer (CRC), that occur in mucosal areas where MAIT cells are abundant. We identify MAIT cells near CRC tumors and show that these areas and precancerous polyps express high levels of the IL-13 receptor, which promotes tumor progression and metastasis. Our data suggest that MAIT cells have a more complicated role in CRC than currently realized and that they represent a promising new target for immunotherapies where IL-13 can be a critical factor.

    更新日期:2019-11-01
  • Polyinosinic-polycytidylic acid induces innate immune responses via Toll-like receptor 3 in human ovarian granulosa cells.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-05-22
    Keqin Yan,Jing Liang,Xiao Zhang,Lin Deng,Dingqing Feng,Bin Ling

    The ovary can be infected by a variety of viruses, which may come from the female reproductive tract or the peritoneum. The innate immune responses to viral infection in the human ovary are poorly understood. The present study demonstrated that human ovarian granulosa cells had innate immune activity in response to viral RNA challenge through Toll-like receptor 3 (TLR3) activation. TLR3 was constitutively expressed in the human ovary and predominantly located in granulosa cells of developmental follicles at all stages. Polyinosinic-polycytidylic acid [poly (I:C)], a synthetic viral double-stranded RNA analog, induced innate immune responses in human ovarian granulosa cells and affected endocrine function. Poly (I:C) significantly upregulated proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1β and type I interferon (IFN-α/β), and the innate immune responses were significantly reduced by blocking TLR3 signaling. Furthermore, poly (I:C) induced antiviral genes expression, including 2'-5'-oligoadenylate synthetase, Mx GTPase 1, IFN-stimulating gene 15 and double-stranded RNA-activated protein kinase R. In contrast, the expression of P450 aromatase and inhibin was dramatically inhibited by poly (I:C). Both silencing of TLR3 and neutralizing TNF-α reversed the inhibitory effect of poly (I:C) on P450 aromatase and inhibin expression. Our study demonstrates that granulosa cells play a potential role in innate immune protection against viral infection in the normal human ovary, and the innate immune response perturbs cell endocrine function.

    更新日期:2019-11-01
  • CARD11 is dispensable for homeostatic responses and suppressive activity of peripherally induced FOXP3+ regulatory T cells.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-05-16
    Antonia Policheni,Keisuke Horikawa,Liz Milla,Jennifer Kofler,Philippe Bouillet,Gabrielle T Belz,Lorraine A O'Reilly,Christopher C Goodnow,Andreas Strasser,Daniel Hd Gray

    FOXP3+ regulatory T (Treg) cells are essential for immunological tolerance and immune homeostasis. Despite a great deal of interest in modulating their number and function for the treatment of autoimmune disease or cancer, the precise mechanisms that control the homeostasis of Treg cells remain unclear. We report a new ENU-induced mutant mouse, lack of costimulation (loco), with atopic dermatitis and Treg cell deficiency typical of Card11 loss-of-function mutants. Three distinct single nucleotide variants were found in the Card11 introns 2, 10 and 20 that cause the loss of CARD11 expression in these mutant mice. These mutations caused the loss of thymic-derived, Neuropilin-1+ (NRP1+ ) Treg cells in neonatal and adult loco mice; however, residual peripherally induced NRP1- Treg cells remained. These peripherally generated Treg cells could be expanded in vivo by the administration of IL-2:anti-IL-2 complexes, indicating that this key homeostatic signaling axis remained intact in CARD11-deficient Treg cells. Furthermore, these expanded Treg cells could mediate near-normal suppression of activated, conventional CD4+ T cells, suggesting that CARD11 is dispensable for Treg cell function. In addition to shedding light on the requirements for CARD11 in Treg cell homeostasis and function, these data reveal novel noncoding Card11 loss-of-function mutations that impair the expression of this critical immune-regulatory protein.

    更新日期:2019-11-01
  • Enhanced safety and immunogenicity of a pneumococcal surface antigen A mutant whole-cell inactivated pneumococcal vaccine.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-05-03
    Shannon C David,Zoe Laan,Vikrant Minhas,Austen Y Chen,Justin Davies,Timothy R Hirst,Shaun R McColl,Mohammed Alsharifi,James C Paton

    Existing capsular polysaccharide-based vaccines against pneumococcal disease are highly effective against vaccine-included serotypes, but they are unable to combat serotype replacement. We have developed a novel pneumococcal vaccine that confers serotype-independent protection, and could therefore constitute a "universal" vaccine formulation. This preparation is comprised of whole un-encapsulated pneumococci inactivated with gamma irradiation (γ-PN), and we have previously reported induction of cross-reactive immunity after nonadjuvanted intranasal vaccination. To further enhance vaccine immunogenicity and safety, we modified the pneumococcal vaccine strain to induce a stressed state during growth. Specifically, the substrate binding component of the psaBCA operon for manganese import was mutated to create a pneumococcal surface antigen A (psaA) defective vaccine strain. psaA mutation severely attenuated the growth of the vaccine strain in vitro without negatively affecting pneumococcal morphology, thereby enhancing vaccine safety. In addition, antibodies raised against vaccine preparations based on the modified strain [γ-PN(ΔPsaA)] showed more diversified reactivity to wild-type pneumococcal challenge strains compared to those induced by the original formulation. The modified vaccine also induced comparable protective TH 17 responses in the lung, and conferred greater protection against lethal heterologous pneumococcal challenge. Overall, the current study demonstrates successful refinement of a serotype-independent pneumococcal vaccine candidate to enhance safety and immunogenicity.

    更新日期:2019-11-01
  • The role of Langerhans cells in pathologies of the skin.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-04-17
    Aarthi Rajesh,Lyn Wise,Merilyn Hibma

    Langerhans cells (LCs) are epidermal immune cells of myeloid origin. Although these cells were primarily thought to play a defensive role in the skin, evidence now indicates a diverse range of LC-mediated effects including the relay of viral antigens in herpes simplex infection, recruitment of eosinophils in atopic dermatitis and promotion of a Th17 response in Candida infection. LCs may have a protective or suppressive function in pathologies of the skin, with differing functions being driven by the skin milieu. Understanding LC function will help guide the development of interventions that modulate these cells for therapeutic benefit.

    更新日期:2019-11-01
  • Effects of IL-10- and FasL-overexpressing dendritic cells on liver transplantation tolerance in a heterotopic liver transplantation rat model.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-04-13
    Lihong Chen,Lina Zhang,Zhu Zhu,Wubing He,Lingyun Gao,Wenmin Zhang,Jingfeng Liu,Aimin Huang

    Acute rejection is the major determinant for the long-term survival of donor liver after liver transplantation (LT). The aim of this study was to examine the therapeutic potential of interleukin (IL)-10-FasL-overexpressing immature dendritic cells (imDCs) to induce local immunosuppression in liver grafts. imDCs derived from donors were transduced by lentiviral vectors expressing human IL-10 and/or Fas ligand (FasL) gene(s), and the expression of surface molecules and the ability to induce T-cell proliferation were measured. imDCs were intraperitoneally injected into recipient rats as a model of LT to examine the rejection grade [Banff rejection activity index (RAI)], liver functions [Alanine aminotransferase, Aspartate aminotransferase (AST) and total bilirubin (TBIL)] and post-transplant survival. IL-10 and FasL co-transduction of imDCs induced a greater reduction in CD80, CD86 and major histocompatibility complex class II (MHC II) expression, as well as T-cell proliferation, but increased levels of IL-10 and FasL in culture supernatants compared with mono-transduced or untransduced imDCs (P < 0.05). The infusion of co-transduced imDCs in LT recipients reduced RAI scores, decreased plasma AST and TBIL, and prolonged survival compared with mono-transduced or untransduced imDC-treated liver allografts. These findings demonstrated that the transfusion of IL-10-FasL/imDCs enhanced immune tolerance and prolonged the survival of liver allografts after LT. The immunomodulatory activity of IL-10- and FasL-modified imDCs might be a new therapeutic approach to prevent organ rejection in clinical transplantation.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • The role of innate immune responses and neuroinflammation in amyloid accumulation and progression of Alzheimer's disease.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-10-28
    Alessandra Webers,Michael T Heneka,Paul A Gleeson

    Alzheimer's disease (AD) is characterized by amyloid beta (Aβ) accumulation, tau pathology and neuroinflammation. Recently, there has been considerable interest in the role of neuroinflammation in directly contributing to the progression of AD. Studies in mice and humans have identified a role for microglial cells, the resident innate immune cells of the central nervous system, in AD. Activated microglia are a key hallmark of the disease and the secretion of proinflammatory cytokines by microglia may result in a positive feedback loop between neurons and microglia, resulting in ongoing low-grade inflammation. Traditionally, the pathways of Aβ production and neuroinflammation have been considered independently; however, recent studies suggest that these processes may converge to promote the pathology associated with AD. Here we review the importance of inflammation and microglia in AD development and effects of inflammatory responses on cellular pathways of neurons, including Aβ generation.

    更新日期:2019-11-01
  • Hyperglycemia aggravates acute liver injury by promoting liver-resident macrophage NLRP3 inflammasome activation via the inhibition of AMPK/mTOR-mediated autophagy induction.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-10-19
    Qi Wang,Song Wei,Shun Zhou,Jiannan Qiu,Chenyu Shi,Rui Liu,Haoming Zhou,Ling Lu

    Although the detrimental effects of diabetes mellitus/hyperglycemia have been observed in many liver disease models, the function and mechanism of hyperglycemia regulating liver-resident macrophages, Kupffer cells (KCs), in thioacetamide (TAA)-induced liver injury remain largely unknown. In this study, we evaluated the role of hyperglycemia in regulating NOD-like receptor family pyrin domain-containing 3 protein (NLRP3) inflammasome activation by inhibiting autophagy induction in KCs in the TAA-induced liver injury model. Type I diabetes/hyperglycemia was induced by streptozotocin treatment. Compared with the control group, hyperglycemic mice exhibited a significant increase in intrahepatic inflammation and liver injury. Enhanced NLRP3 inflammasome activation was detected in KCs from hyperglycemic mice, as shown by increased gene induction and protein levels of NLRP3, cleaved caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain and interleukin-1β, compared with control mice. NLRP3 inhibition by its antagonist CY-09 effectively suppressed inflammasome activation in KCs and attenuated liver injury in hyperglycemic mice. Furthermore, inhibited autophagy activation was revealed by transmission electron microscope detection, decreased LC3B protein expression and p-62 protein degradation in KCs isolated from TAA-stressed hyperglycemic mice. Interestingly, inhibited 5' AMP-activated protein kinase (AMPK) but enhanced mammalian target of rapamycin (mTOR) activation was found in KCs from TAA-stressed hyperglycemic mice. AMPK activation by its agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or mTOR signaling knockdown by small interfering RNA restored autophagy activation, and subsequently, inhibited NLRP3 inflammasome activation in KCs, leading to ultimately reduced TAA-induced liver injury in the hyperglycemic mice. Our findings demonstrated that hyperglycemia aggravated TAA-induced acute liver injury by promoting liver-resident macrophage NLRP3 inflammasome activation via inhibiting AMPK/mTOR-mediated autophagy. This study provided a novel target for prevention of toxin-induced acute liver injury under hyperglycemia.

    更新日期:2019-11-01
  • Systems immunology reveals a linked IgG3-C4 response in patients with acute rheumatic fever.
    Immunol. Cell Biol. (IF 3.947) Pub Date : null
    Amy W Chung,Timothy Kc Ho,Paulina Hanson-Manful,Susanne Tritscheller,Jeremy M Raynes,Alana L Whitcombe,Mei Lin Tay,Reuben McGregor,Natalie Lorenz,Jane R Oliver,Jason K Gurney,Cristin G Print,Nigel J Wilson,William J Martin,Deborah A Williamson,Michael G Baker,Nicole J Moreland

    Acute rheumatic fever (ARF) and chronic rheumatic heart disease (RHD) are autoimmune sequelae of a Group A streptococcal infection with significant global mortality and poorly understood pathogenesis. Immunoglobulin and complement deposition were observed in ARF/RHD valve tissue over 50 years ago, yet contemporary investigations have been lacking. This study applied systems immunology to investigate the relationships between the complement system and immunoglobulin in ARF. Patients were stratified by C-reactive protein (CRP) concentration into high (≥10 μg mL-1 ) and low (<10 μg mL-1 ) groups to distinguish those with clinically significant inflammatory processes from those with abating inflammation. The circulating concentrations of 17 complement factors and six immunoglobulin isotypes and subclasses were measured in ARF patients and highly matched healthy controls using multiplex bead-based immunoassays. An integrative statistical approach combining feature selection and principal component analysis revealed a linked IgG3-C4 response in ARF patients with high CRP that was absent in controls. Strikingly, both IgG3 and C4 were elevated above clinical reference ranges, suggesting these features are a marker of ARF-associated inflammation. Humoral immunity in response to M protein, an antigen implicated in ARF pathogenesis, was completely polarized to IgG3 in the patient group. Furthermore, the anti-M-protein IgG3 response was correlated with circulating IgG3 concentration, highlighting a potential role for this potent immunoglobulin subclass in disease. In conclusion, a linked IgG3-C4 response appears important in the initial, inflammatory stage of ARF and may have immediate utility as a clinical biomarker given the lack of specific diagnostic tests currently available.

    更新日期:2019-11-01
  • TACI expression and plasma cell differentiation are impaired in the absence of functional IκBNS.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-01-01
    Sharesta Khoenkhoen,Elina Erikson,Monika Ádori,Julian M Stark,Jean L Scholz,Michael P Cancro,Gabriel K Pedersen,Gunilla B Karlsson Hedestam

    Impaired classical NF-κB pathway signaling causes reduced antibody responses to T-independent (TI) antigens. We investigated the potential reasons for defective TI responses in mice lacking the atypical inhibitory kappa B (IκB) protein of the NF-κB pathway, IκBNS. Analyses of the plasma cell compartment in vitro and in vivo after challenge with lipopolysaccharide (LPS) showed significant decreases in the frequencies of plasma cells in the absence of IκBNS. In vitro activation of B cells via the B cell receptor or via Toll-like receptor 4 revealed that early activation events were unaffected in IκBNS-deficient B cells, while proliferation was reduced compared to in similarly stimulated wildtype (wt) B cells. IκBNS-deficient B cells also displayed impaired upregulation of the transmembrane activator and calcium modulator cyclophilin ligand interactor (TACI), which is essential for TI responses, and decreased sensitivity to TACI ligands upon stimulation. Furthermore, IκBNS-deficient B cells, in contrast to wt B cells, displayed altered expression of IRF4, Blimp-1 and Pax5 upon LPS-induced differentiation, indicating impaired transcriptional regulation of plasma cell generation.

    更新日期:2019-11-01
  • Going deeper: three-dimensional study of γδ T cells in mouse reproductive tract using tissue clearing methods.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2018-09-16
    Katarzyna Mikolajewicz,Grzegorz Chodaczek

    Several tissue clearing methods have been developed for three-dimensional imaging of thick specimens. Here, we applied CUBIC and ScaleS approaches to whole-mounted vaginal wall to reveal spatial distribution of γδ T lymphocytes, the key cells engaged in the epithelial homeostasis control and immune surveillance. Both methods rendered the tissue transparent and enabled detection of the green fluorescent protein (GFP)-expressing γδ T cells in vaginal samples of Tcrd-H2BeGFP transgenic mice. Upon additional immunolabeling, however, only CUBIC preserved the GFP signal and allowed for cell localization assessment during the estrous cycle. Using a combination of single- and two-photon microscopy, we found that during the diestrus phase the number of γδ T cells in the vaginal wall increased compared to estrus, while the proportion of cells residing in epithelium and stroma remained constant, irrespective of the cycle phase, and was close to 3:1, respectively. Moreover, the distance from epithelial γδ T cells to laminin-positive basal membrane and collagen-rich stroma also increased in diestrus in spite of thinning of epithelium upon shedding cornified cells. Our data indicate that γδ T cells sense sex hormone fluxes which influence their number and position them closer to the vaginal lumen in the diestrus phase.

    更新日期:2019-11-01
  • Histone deacetylase 2 is essential for LPS-induced inflammatory responses in macrophages.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2018-09-13
    Chenming Wu,Ang Li,Jian Hu,Jiuhong Kang

    The role of specific histone deacetylase (HDAC) proteins in regulating the lipopolysaccharide (LPS)-induced inflammatory response and its underlying mechanisms are unclear. Here, HDAC2, a class I HDAC family protein, is essential for the LPS-triggered inflammatory response in macrophages. LPS stimulation increases HDAC2 expression in macrophages. Knockdown of HDAC2 decreases the expression of proinflammatory genes, such as IL-12, TNF-α and iNOS following stimulation with LPS. The adoptive transfer of HDAC2 knockdown macrophages attenuates the LPS-triggered innate inflammatory response in vivo, and these mice are less sensitive to endotoxin shock and Escherichia coli-induced sepsis. Mechanistically, the c-Jun protein is the main target of HDAC2-mediated LPS-induced production of proinflammatory cytokines. Moreover, HDAC2 knockdown increases the expression of c-Jun, which directly binds the promoters of proinflammatory genes and forms nuclear receptor corepressor complexes to inhibit the transcription of proinflammatory genes in macrophages. These effects are rescued by c-Jun expression. According to the chromatin immunoprecipitation analysis, HDAC2 also selectively suppresses c-Jun expression by directly binding to its promoter and modifying histone acetylation after LPS stimulation. Our findings define a new function and mechanism of the HDAC2/c-Jun signaling network that regulates the LPS-induced immune response in macrophages.

    更新日期:2019-11-01
  • Early-life exposure to gut microbiota from disease-protected mice does not impact disease outcome in type 1 diabetes susceptible NOD mice.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2018-09-08
    Jane A Mullaney,Juliette E Stephens,Brooke E Geeling,Emma E Hamilton-Williams

    The microbial community making up the gut microbiota can profoundly influence intestinal homeostasis and immune system development, and is believed to influence the development of complex diseases including type 1 diabetes (T1D). T1D susceptible nonobese diabetic (NOD) mice have been shown to harbor a distinct microbiota to disease-protected mice. We hypothesized that the T1D susceptible genetic background of NOD mice would be resistant to the introduction of a C57BL/6-derived microbiota. NOD and C57BL/6 mice were cohoused either continually from birth, from birth until weaning or from weaning onwards, allowing transfer of microbiota between the mice. Cohousing NOD with C57BL/6 mice from before birth, resulted in moderate changes to the gut microbiota, whereas initiating cohousing at weaning only led to minimal changes. Terminating cohousing at weaning reduced the changes in the microbiota composition. However, diabetes onset was not significantly delayed and there was no reduction in intestinal inflammation or the proportion of regulatory T cells in the cohoused NOD mice. However, insulin but not islet-specific glucose-6-phosphatase catalytic subunit-related protein-specific CD8+ T cells were reduced by cohousing suggesting an epitope-specific modulation of the autoreactive response by the gut microbiota. These results suggest that the T1D susceptible genetic background of the NOD mouse was resistant to the introduction of a C57BL/6-derived microbiota.

    更新日期:2019-11-01
  • IL-33 regulates cytokine production and neutrophil recruitment via the p38 MAPK-activated kinases MK2/3.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2018-09-02
    Pierre C McCarthy,Iain R Phair,Corinna Greger,Katerina Pardali,Victoria A McGuire,Andrew R Clark,Matthias Gaestel,J Simon C Arthur

    IL-33 is an IL-1-related cytokine that can act as an alarmin when released from necrotic cells. Once released, it can target various immune cells including mast cells, innate lymphoid cells and T cells to elicit a Th2-like immune response. We show here that bone marrow-derived mast cells produce IL-13, IL-6, TNF, GM-CSF, CCL3 and CCL4 in response to IL-33 stimulation. Inhibition of the p38 MAPK, or inhibition or knockout of its downstream kinases MK2 and MK3, blocked the production of these cytokines in response to IL-33. The mechanism downstream of MK2/3 was cytokine specific; however, MK2 and MK3 were able to regulate TNF and GM-CSF mRNA stability. Previous studies in macrophages have shown that MK2 regulates mRNA stability via phosphorylation of the RNA-binding protein TTP (Zfp36). The regulation of cytokine production in mast cells was, however, independent of TTP. MK2/3 were able to phosphorylate the TTP-related protein Brf1 (Zfp36 l1) in IL-33-stimulated mast cells, suggesting a mechanism by which MK2/3 might control mRNA stability in these cells. In line with its ability to regulate in vitro IL-33-stimulated cytokine production, double knockout of MK2 and 3 in mice prevented neutrophil recruitment following intraperitoneal injection of IL-33.

    更新日期:2019-11-01
  • Genetic regulation of antibody responsiveness to immunization in substrains of BALB/c mice.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2018-08-29
    Hazel C Poyntz,Angela Jones,Ruy Jauregui,Wayne Young,Aurélie Gestin,Anna Mooney,Olivier Lamiable,Eric Altermann,Alfonso Schmidt,Olivier Gasser,Laura Weyrich,Christopher J Jolly,Michelle A Linterman,Graham Le Gros,Edwin D Hawkins,Elizabeth Forbes-Blom

    Antibody-mediated immunity is highly protective against disease. The majority of current vaccines confer protection through humoral immunity, but there is high variability in responsiveness across populations. Identifying immune mechanisms that mediate low antibody responsiveness may provide potential strategies to boost vaccine efficacy. Here, we report diverse antibody responsiveness to unadjuvanted as well as adjuvanted immunization in substrains of BALB/c mice, resulting in high and low antibody response phenotypes. Furthermore, these antibody phenotypes were not affected by changes in environmental factors such as the gut microbiota composition. Antigen-specific B cells following immunization had a marked difference in capability to class switch, resulting in perturbed IgG isotype antibody production. In vitro, a B-cell intrinsic defect in the regulation of class-switch recombination was identified in mice with low IgG antibody production. Whole genome sequencing identified polymorphisms associated with the magnitude of antibody produced, and we propose candidate genes that may regulate isotype class-switching capability. This study highlights that mice sourced from different vendors can have significantly altered humoral immune response profiles, and provides a resource to interrogate genetic regulators of antibody responsiveness. Together these results further our understanding of immune heterogeneity and suggest additional research on the genetic influences of adjuvanted vaccine strategies is warranted for enhancing vaccine efficacy.

    更新日期:2019-11-01
  • Constitutive overexpression of TNF in BPSM1 mice causes iBALT and bone marrow nodular lymphocytic hyperplasia.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2018-08-15
    Cyril Seillet,Elysa Carr,Derek Lacey,Michael D Stutz,Marc Pellegrini,Lachlan Whitehead,Joel Rimes,Edwin D Hawkins,Ben Roediger,Gabrielle T Belz,Philippe Bouillet

    BPSM1 (Bone phenotype spontaneous mutant 1) mice develop severe polyarthritis and heart valve disease as a result of a spontaneous mutation in the Tnf gene. In these mice, the insertion of a retrotransposon in the 3' untranslated region of Tnf causes a large increase in the expression of the cytokine. We have found that these mice also develop inducible bronchus-associated lymphoid tissue (iBALT), as well as nodular lymphoid hyperplasia (NLH) in the bone marrow. Loss of TNFR1 prevents the development of both types of follicles, but deficiency of TNFR1 in the hematopoietic compartment only prevents the iBALT and not the NLH phenotype. We show that the development of arthritis and heart valve disease does not depend on the presence of the tertiary lymphoid tissues. Interestingly, while loss of IL-17 or IL-23 limits iBALT and NLH development to some extent, it has no effect on polyarthritis or heart valve disease in BPSM1 mice.

    更新日期:2019-11-01
  • Transfection reagent Lipofectamine triggers type I interferon signaling activation in macrophages.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2018-08-08
    Xiaomin Guo,Huan Wang,Yang Li,Xiaopeng Leng,Weiwei Huang,Yanbing Ma,Tao Xu,Xiaopeng Qi

    The commercial transfection reagent Lipofectamine has been widely used for cytoplasmic delivery of nucleic acids and for cytosolic engagement with intracellular innate immune sensors to trigger type I interferon (IFN) production. However, the effect of Lipofectamine alone on type I IFN response has not been studied in detail. Here, we show that Lipofectamine induced type I IFN signaling in both RAW 264.7 macrophage-like cells and primary bone marrow-derived macrophages. Type I IFN induction was dependent on interferon regulatory factor (IRF)3 and IRF7 and partially required the toll/interleukin-1 receptor-domain-containing adapter-inducing interferon-β. In contrast, the transfection reagent Xfect did not activate type I IFN signaling. Our study highlights the potential confounding experimental interpretation when using Lipofectamine-based transfection for delivering intracellular ligands and provides important insights into lipid signaling in innate immune responses.

    更新日期:2019-11-01
  • Compromised NLRP3 and AIM2 inflammasome function in autoimmune NZB/W F1 mouse macrophages.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2018-07-28
    Sara J Thygesen,Karli E Takizawa,Avril A B Robertson,David P Sester,Katryn J Stacey

    Inflammasomes are protein complexes activated by infection and cellular stress that promote caspase-1 activation and subsequent inflammatory cytokine processing and cell death. It has been anticipated that inflammasome activity contributes to autoimmunity. However, we previously showed that macrophages from autoimmune New Zealand Black (NZB) mice lack NLRP3 inflammasome function, and their absent in melanoma 2 (AIM2) inflammasome responses are compromised by high expression of the AIM2 antagonist protein p202. Here we found that the point mutation leading to lack of NLRP3 expression occurred early in the NZB strain establishment, as it is shared with the related obese strain New Zealand Obese, but not with the unrelated New Zealand White (NZW) strain. The first cross progeny of NZB and NZW mice develop more severe lupus nephritis than the NZB strain. We have compared AIM2 and NLRP3 inflammasome function in macrophages from NZB, NZW, and NZB/W F1 mice. The NZW parental strain showed strong inflammasome function, whereas the NZB/W F1 have haploinsufficient expression of NLRP3 and show reduced NLRP3 and AIM2 inflammasome responses, particularly at low stimulus strength. It remains to be established whether the low inflammasome function could contribute to loss of tolerance and the onset of autoimmunity in NZB and NZB/W F1. However, with amplifying inflammatory stimuli through the course of disease, the NLRP3 response in the NZB/W F1 may be sufficient to contribute to kidney damage at later stages of disease.

    更新日期:2019-11-01
  • Intranasal immunization with recombinant chlamydial protease-like activity factor attenuates atherosclerotic pathology following Chlamydia pneumoniae infection in mice.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2018-07-28
    Weidang Li,Pareesha Gudipaty,Chuxi Li,Kyle K Henderson,Kyle H Ramsey,Ashlesh K Murthy

    We have shown previously that intranasal vaccination with recombinant chlamydial protease-like activity factor (rCPAF: antigen) and interleukin-12 (IL-12) as an adjuvant induces robust protection against pathological consequences of female genital tract infection with Chlamydia muridarum, a closely related species and a rodent model for the human pathogen Chlamydia trachomatis. Another related species Chlamydia pneumoniae, a human respiratory pathogen, has been associated with exacerbation of atherosclerotic pathology. CPAF is highly conserved among Chlamydia spp. leading us to hypothesize that immunization with rCPAF with IL-12 will protect against high-fat diet (HFD) and C. pneumoniae-induced acceleration of atherosclerosis. rCPAF ± IL-12 immunization induced robust splenic antigen (Ag)-specific IFN-γ and TNF-α production and significantly elevated serum total anti-CPAF Ab, IgG2c, and IgG1 antibody levels compared to mock or IL-12 alone groups. The addition of IL-12 to rCPAF significantly elevated splenic Ag-specific IFN-γ production and IgG2c/IgG1 anti-CPAF antibody ratio. Following intranasal C. pneumoniae challenge and HFD feeding, rCPAF ± IL-12-immunized mice displayed significantly enhanced splenic IFN-γ, not TNF-α, response on days 6 and 9 after challenge, and significantly reduced lung chlamydial burden on day 9 post-challenge compared to mock- or IL-12-immunized mice. Importantly, rCPAF ± IL-12-immunized mice displayed significantly reduced atherosclerotic pathology in the aortas after C. pneumoniae challenge. Serum cholesterol levels were comparable between the groups suggesting that the observed differences in pathology were due to protective immunity against the infection. Together, these results confirm and extend our previous observations that CPAF is a promising candidate antigen for a multisubunit vaccine regimen to protect against Chlamydia-induced pathologies, including atherosclerosis.

    更新日期:2019-11-01
  • The immune system and stroke: from current targets to future therapy.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2018-07-20
    Kyle Malone,Sylvie Amu,Anne C Moore,Christian Waeber

    Stroke is a major cause of morbidity and mortality worldwide. Despite the intensive search for new therapies, hundreds of agents targeting various pathophysiological mechanisms have failed clinical trials, and the thrombolytic agent tissue plasminogen activator is currently the only FDA-approved medication for the treatment of acute ischemic stroke. The immune system is involved in all stages of stroke, from the pathogenesis of risk factors to neurotoxicity, to tissue remodeling and repair. There is a bidirectional interaction between the brain and the immune system, with stroke-induced immunosuppression and subsequent infection a principal source of patient mortality. Newer work also points to a role for the gut microbiota in the immune response to stroke, while clinical sequelae such as dementia might now also be explained in immune terms. However, the exact roles of innate and adaptive components have not been fully elucidated, with studies reporting both detrimental and beneficial functions. Time is a key determinant in defining whether immunity and inflammation are neuroprotective or neurotoxic. The local inflammatory milieu also has a clear influence on many proposed treatments. This review examines the individual components of the immune response to stroke, highlighting the most promising future stroke immunotherapies.

    更新日期:2019-11-01
  • Controlled detonation: evolution of necroptosis in pathogen defense.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2016-12-03
    Michelle Brault,Andrew Oberst

    Necroptosis is a lytic form of programmed cell death that involves the swelling and rupture of dying cells. Although several necroptosis-inducing stimuli have been defined, in most cells this pathway is kept in check by the action of the pro-apoptotic protease caspase-8 and the IAP ubiquitin ligases. How and when necroptosis is triggered under physiological conditions therefore remains a persistent question. Because necroptosis likely arose as a defensive mechanism against viral infection, exploration of this question requires a consideration of host-pathogen interactions, and how the sensing of infection could sensitize cells to necroptosis. Here, we will discuss the role of necroptosis in the response to viral infection, consider why the necroptotic pathway has been favored during evolution, and describe emerging evidence for death-independent functions of key necroptotic signaling components.

    更新日期:2019-11-01
  • CD244 is expressed on dendritic cells and regulates their functions.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2015-02-04
    Anna-Maria Georgoudaki,Sorosh Khodabandeh,Speranta Puiac,Catrine M Persson,Maria K Larsson,Max Lind,Oscar Hammarfjord,Tara H Nabatti,Robert P A Wallin,Ulf Yrlid,Mikael Rhen,Vinay Kumar,Benedict J Chambers

    Signaling lymphocytic activation molecule (SLAM) receptors have an important role in the development of immune responses because of their roles, for exampe, in NK cell cytotoxicity and cytokine production by NK, T cells and myeloid cells. The SLAM receptor CD244 (2B4, SLAMf4) is expressed on a variety of immune cell types but most of its functions have been examined on NK and T cells. In the present study, we investigated expression and function of CD244 in murine subsets of dendritic cells (DCs). We report that all subsets of murine DCs examined expressed CD244, although the expression levels of CD244 varied between subsets. Splenic and resident mesenteric lymph node (MLN) DCs from CD244(-/-) mice expressed lower levels of CD86 and MHC class II compared with wild-type mice. Upon Toll-like receptor (TLR) stimulation, no differences in surface expression of these molecules were observed between DCs from CD244(-/-) and wild-type mice. However, splenic DCs from CD244(-/-) mice upon stimulation with TLR binding ligands lipopolysaccharide (LPS) and CpG produced significantly higher levels of pro-inflammatory cytokines. In addition, DCs from CD244(-/-) mice elicited increased NK cell activation in vitro. These data add CD244 to a growing list of immuno-modulatory receptors found on DCs.

    更新日期:2019-11-01
  • Lysophosphatidylserine suppression of T-cell activation via GPR174 requires Gαs proteins.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2018-02-20
    Michael J Barnes,Jason G Cyster

    G protein-coupled receptors regulate diverse aspects of T-cell activity and effector function. Recently, we showed that GPR174 mediates the suppression of T-cell proliferation in vitro induced by the polar lipid lysophosphatidylserine (LysoPS). Here, we investigated the in vivo activity of this pathway and characterized the mechanisms involved. Using in vivo models of T-cell proliferation induced by sublethal irradiation or regulatory T-cell depletion, we show that GPR174 expression can constrain T-cell proliferation. In vitro experiments established that Gαs G proteins are needed for LysoPS/GPR174-mediated suppression of T-cell proliferation. Mechanistically, LysoPS acts via GPR174 and Gαs to suppress IL-2 production by activated T cells and limit upregulation of the activation markers CD25 and CD69. Together, our findings identify GPR174 as an abundantly expressed Gαs-dependent receptor that can negatively regulate naive T-cell activation. See also: News and Commentary by Robert & Mackay.

    更新日期:2019-11-01
  • Immunological memory.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-07-10
    Joanna R Kirman,Kylie M Quinn,Robert A Seder

    更新日期:2019-11-01
  • Beyond memory T cells: mechanisms of protective immunity to tuberculosis infection.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-05-30
    Pia Steigler,Ayesha J Verrall,Joanna R Kirman

    Tuberculosis (TB) is a serious infectious disease caused by infection with Mycobacterium tuberculosis, and kills more people annually than any other single infectious agent. Although a vaccine is available, it is only moderately effective and an improved vaccine is urgently needed. The ability to develop a more effective vaccine has been thwarted by a lack of understanding of the mechanism of vaccine-induced immune protection. Over recent decades, many novel TB vaccines have been developed and almost all have aimed to generate memory CD4 T cells. In this review, we critically evaluate evidence in the literature that supports the contention that memory CD4 T cells are the prime mediators of vaccine-induced protection against TB. Because of the lack of robust evidence supporting memory CD4 T cells in this role, the potential for B-cell antibody and "trained" innate cells as alternative mediators of protective immunity is explored.

    更新日期:2019-11-01
  • Similar but different: virtual memory CD8 T cells as a memory-like cell population.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-05-30
    Tabinda Hussain,Kylie M Quinn

    Immunological memory is a phenomenon where the immune system can respond more rapidly to pathogens and immunological challenges that it has previously encountered. It is defined by several key hallmarks. After an initial encounter, immune cells (1) expand and (2) differentiate to form memory cell populations. Memory cells are (3) long-lived and (4) facilitate more rapid immune responses to subsequent infection because of (i) an increase in cell number, (ii) a decrease in the signaling threshold required for entry into cell cycle or effector function and (iii) localization of cells to tissue sites for surveillance. Classically, immunological memory has been antigen specific but it is becoming apparent that mechanisms of immunological memory can be co-opted by innate or antigen-inexperienced immune cells to generate heterogeneity in immune responses. One such cell is the virtual memory CD8 T (TVM ) cell, which is a semi-differentiated but antigen-naïve CD8 T-cell population. This review will summarize current knowledge of how TVM cells are generated, their memory-like hallmarks, how they are maintained during steady state, infection and aging, and propose a model to integrate key signaling pathways during their generation.

    更新日期:2019-11-01
  • The metabolic spectrum of memory T cells.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-05-28
    David O'Sullivan

    The development and persistence of memory T cells are integral to effective host defenses. Cell metabolism has a central role in the maintenance of these populations and engagement of specific metabolic pathways can influence T-cell fate. Nuances in memory T-cell metabolism are both context dependent, and exist, on a spectrum that complements and supports the activity of specific memory T-cell subsets. This review explores how metabolic pathways and substrate choice can influence the phenotype and function of memory T cells.

    更新日期:2019-11-01
  • The generation of T-cell memory to protect against tuberculosis.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-05-28
    Claudio Counoupas,James A Triccas

    Tuberculosis (TB) kills more individuals each year than any other single pathogen and a more effective vaccine is critical for the global control of the disease. Although there has been recent progress in the clinical testing of candidates, no new vaccine has been licensed for use and correlates of protective immunity in humans have not been defined. Prior Mycobacterium tuberculosis infection does not appear to confer long-term protective immunity in humans; thus mimicking the natural immune response to infection may not be a suitable approach to develop improved TB vaccines. Data from animal testing are used to progress vaccines through the "vaccine pipeline", but studies in animals have not been able to predict efficacy in humans. Furthermore, although the generation of conventional CD4+ T-cell responses are considered necessary to control infection with M. tuberculosis, these do not necessarily correlate with protection induced by candidate vaccines and other immune components may play a role, including donor unrestricted T cells, tissue-resident memory T cells and anti-M. tuberculosis antibodies. This review will summarize the current understanding of the protective immune responses following M. tuberculosis infection or vaccination, with a particular focus on vaccines that have recently entered clinical trials.

    更新日期:2019-11-01
  • The microbiome and immune memory formation.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-05-28
    Kathy D McCoy,Regula Burkhard,Markus B Geuking

    The microbiota plays an important role in regulating both the innate and adaptive immune systems. Many studies have focused on the ability of microbes to shape the immune system by stimulating B-cell and antibody responses and the differentiation of T helper cell function. However, an important feature of the immune system is its ability to generate memory responses, which provide increased survival for the host. This review will highlight the role of the microbiota in the induction of immune memory with a focus on both adaptive and innate memory as well as vaccine efficacy.

    更新日期:2019-11-01
  • Development of circulating CD4+ T-cell memory.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-05-24
    Megan Sf Soon,Jessica A Engel,Hyun J Lee,Ashraful Haque

    The ability of circulating CD4+ T cells to retain memories of previous antigenic encounters is a cardinal feature of the adaptive immune system. Over the past two decades, since the first description of central and effector memory T cells, many studies have examined molecular mechanisms controlling CD8+ T-cell memory, with comparatively less research into CD4+ T-cell memory. Here, we review a number of seminal studies showing that circulating memory CD4+ T cells develop directly from effector cells; and in so doing, preserve features of their effector precursors. We examine mechanisms controlling the development and phenotypes of memory CD4+ T cells, and provide an updated model that accommodates both the central and effector memory paradigm and the diverse T helper cell classification system.

    更新日期:2019-11-01
  • Chimeric antigen receptor T cell persistence and memory cell formation.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-04-23
    Alexander D McLellan,Seyed M Ali Hosseini Rad

    It is now becoming clear that less differentiated naive and memory T cells are superior to effector T cells in the transfer of immunity for adoptive cell therapy. This review will outline the challenges faced by chimeric antigen receptor (CAR) T cell therapy in the generation of persistence and memory for CAR T cells, and summarize recent strategies to improve CAR T cell persistence, with a focus on memory cell formation. The relevance of enhancing persistence in more differentiated effector T cells is also covered, because genetic and pharmacological interventions may prolong effector T cell activity and lifespan, thereby improving anti-cancer activity. In particular, it may be possible to enforce epigenetic changes in differentiated T cells to enhance memory CAR T cell formation. Optimizing the generation of self-renewing T cell populations (e.g. memory cells), while maintaining differentiated effector T cells through epigenome modification, will help overcome barriers to T cell expansion and survival, thereby improving clinical outcomes in CAR T cell therapy.

    更新日期:2019-11-01
  • Isolation of functional mature peritoneal macrophages from healthy humans.
    Immunol. Cell Biol. (IF 3.947) Pub Date : null
    Antonio J Ruiz-Alcaraz,Helios Martínez-Banaclocha,Pilar Marín-Sánchez,Violeta Carmona-Martínez,Miguel Angel Iniesta-Albadalejo,María Tristán-Manzano,Ana Tapia-Abellán,Pilar García-Peñarrubia,Francisco Machado-Linde,Pablo Pelegrín,María Martínez-Esparza

    Macrophages play an important role in the inflammatory response. Their various biological functions are induced by different membrane receptors, including Toll-like receptors, which trigger several intracellular signalling cascades and activate the inflammasomes, which in turn elicit the release of inflammatory mediators such as cytokines. In this study, we present a novel method for the isolation of human mature peritoneal macrophages. This method can be easily implemented by gynaecologists who routinely perform laparoscopy for sterilization by tubal ligation or surgically intervene in benign gynaecological pathologies. Our method confirms that macrophages are the main peritoneal leukocyte subpopulation isolated from the human peritoneum in homeostasis. We showed that primary human peritoneal macrophages present phagocytic and oxidative activities, and respond to activation of the main pro-inflammatory pathways such as Toll-like receptors and inflammasomes, resulting in the secretion of different pro-inflammatory cytokines. Therefore, this method provides a useful tool for characterizing primary human macrophages as control cells for studies of molecular inflammatory pathways in steady-state conditions and for comparing them with those obtained from pathologies involving the peritoneal cavity. Furthermore, it will facilitate advances in the screening of anti-inflammatory compounds in the human system.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Partial loss of actin nucleator Actin Related Protein 2/3 activity triggers blebbing in primary T lymphocytes.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-11-08
    Peyman Obeidy,Lining Arnold Ju,Stefan H Oehlers,Nursafwana S Zulkhernain,Quintin Lee,Jorge L Galeano,Niño,Rain Kwan,Shweta Tikoo,Lois L Cavanagh,Paulus Mrass,Adam Cook,Shaun P Jackson,Maté Biro,Ben Roediger,Michael Sixt,Wolfgang Weninger

    T lymphocytes utilize amoeboid migration to navigate effectively within complex microenvironments. The precise rearrangement of the actin cytoskeleton required for cellular forward propulsion is mediated by actin regulators, including the Arp2/3 complex, a macromolecular machine that nucleates branched actin filaments at the leading edge. The consequences of modulating Arp2/3 activity on the biophysical properties of the actomyosin cortex and downstream T cell function are incompletely understood. We report that even a moderate decrease of Arp3 levels in T cells profoundly affects actin cortex integrity. Reduction in total F-actin content leads to reduced cortical tension and disrupted lamellipodia formation. Instead, in Arp3-knockdown cells the motility mode is dominated by blebbing migration characterized by transient, balloon-like protrusions at the leading edge. Although this migration mode seems to be compatible with interstitial migration in three-dimensional environments, diminished locomotion kinetics and impaired cytotoxicity interfere with optimal T cell function. These findings define the importance of finely-tuned, Arp2/3-dependent mechanophysical membrane integrity in CTL activities.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Cystatin C regulates major histocompatibility complex-II-peptide presentation and extracellular signal-regulated kinase-dependent polarizing cytokine production by bone marrow-derived dendritic cells.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-09-13
    Wenjie Zhang,Mengting Zi,Li Sun,Fengge Wang,Shun Chen,Yanfang Zhao,Shuangchao Liang,Jiqiong Hu,Shan Liu,Lei Liu,Yifan Zhan,Andrew M Lew,Yuekang Xu

    Cystatin C is a ubiquitously expressed cysteine protease inhibitor that protects cells from either improper hydrolysis by endogenous proteases or pathogen growth/virulence by exogenous proteases. Although commonly used as a serum biomarker for evaluating renal function, cystatin C is associated with many immunological disorders under various pathophysiological conditions. How cystatin C affects immune cells, especially dendritic cells (DCs), however, is far from clear. In this study, we found that pharmacological treatment with or genetic overexpression of cystatin C in bone marrow-derived DCs (BMDCs) reduced their capacity to stimulate CD4+ T-cell proliferation, despite increased antigen uptake. This reduced capacity corresponded with reduced major histocompatibility complex-II presentation owing to diminished levels of the chaperon H2-DM in BMDCs. Instead of promoting proliferation, cystatin C promoted skewing of T cells toward proinflammatory T-helper (Th)1/Th17 differentiation. This was mediated by augmented extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase phosphorylation in BMDCs, leading to secretion of polarizing cytokines, which in turn led to the Th deviation. Collectively, our study explained the cellular and molecular basis of how this protease inhibitor can regulate immune responses, namely by affecting BMDCs and their cytokine pathway. Our results might open up an avenue for the development of therapeutic agents for the treatment of cystatin C-related immunological diseases.

    更新日期:2019-11-01
  • LDK378 inhibits the recruitment of myeloid-derived suppressor cells to spleen via the p38-GRK2-CCR2 pathway in mice with sepsis.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-09-01
    Jie Hu,Wenqin Zhang,Yanjuan Liu,Yang Yang,Chuyi Tan,Xue Wei,Yufang Wang,Sipin Tan,Meidong Liu,Ke Liu,Ying Liu,Huali Zhang,Xianzhong Xiao

    Myeloid-derived suppressor cells (MDSCs) are functionally immunosuppressive cells that are persistently increased in abundance and associated with adverse clinical outcomes in sepsis. Here, we investigated the therapeutic potential of an anaplastic lymphoma kinase inhibitor, LDK378, in cecal ligation and puncture (CLP)-induced polymicrobial sepsis and examined its effects on the recruitment of MDSCs. LDK378 significantly improved the survival of CLP-induced polymicrobial septic mice, which was paralleled by reduced organ injury, decreased release of inflammatory cytokines and decreased recruitment of MDSCs to the spleen. Importantly, LDK378 inhibited the migration of MDSCs to the spleen by blocking the CLP-mediated upregulation of CC chemokine receptor 2 (CCR2), a chemokine receptor critical for the recruitment of MDSCs. Mechanistically, LDK378 treatment blocked the CLP-induced CCR2 upregulation of MDSCs via partially inhibiting the phosphorylation of p38 and G-protein-coupled receptor kinase-2 (GRK2) in bone marrow MDSCs of septic mice. Furthermore, in vitro experiments also showed that lipopolysaccharide (LPS)-induced migration of MDSCs was similarly owing to the activation of GRK2 and upregulation of CCR2 by LPS, whereas the treatment with LDK378 partially blocked the LPS-induced phosphorylation of p38 and GRK2 and decreased the expression of CCR2 on the cell surface, therefore leading to the suppression of MDSC migration. Together, these findings unravel a novel function of LDK378 in the host response to infection and suggest that LDK378 could be a potential therapeutic agent for sepsis.

    更新日期:2019-11-01
  • A comparison of immunoglobulin IGHV, IGHD and IGHJ genes in wild-derived and classical inbred mouse strains.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-08-24
    Corey T Watson,Justin T Kos,William S Gibson,Leah Newman,Gintaras Deikus,Christian E Busse,Melissa L Smith,Katherine Jl Jackson,Andrew M Collins

    The genomes of classical inbred mouse strains include genes derived from all three major subspecies of the house mouse, Mus musculus. We recently posited that genetic diversity in the immunoglobulin heavy chain (IGH) gene loci of C57BL/6 and BALB/c mice reflects differences in subspecies origin. To investigate this hypothesis, we conducted high-throughput sequencing of IGH gene rearrangements to document IGH variable (IGHV), joining (IGHJ) and diversity (IGHD) genes in four inbred wild-derived mouse strains (CAST/EiJ, LEWES/EiJ, MSM/MsJ and PWD/PhJ) and a single disease model strain (NOD/ShiLtJ), collectively representing genetic backgrounds of several major mouse subspecies. A total of 341 germline IGHV sequences were inferred in the wild-derived strains, including 247 not curated in the international ImMunoGeneTics information system. By contrast, 83/84 inferred NOD IGHV genes had previously been observed in C57BL/6 mice. Variability among the strains examined was observed for only a single IGHJ gene, involving a description of a novel allele. By contrast, unexpected variation was found in the IGHD gene loci, with four previously unreported IGHD gene sequences being documented. Very few IGHV sequences of C57BL/6 and BALB/c mice were shared with strains representing major subspecies, suggesting that their IGH loci may be complex mosaics of genes of disparate origins. This suggests a similar level of diversity is likely present in the IGH loci of other classical inbred strains. This must now be documented if we are to properly understand interstrain variation in models of antibody-mediated disease.

    更新日期:2019-11-01
  • Differential interferon-gamma production potential among naïve CD4+ T cells exists prior to antigen encounter.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-08-20
    Aditi Sood,Marie-Ève Lebel,Marilaine Fournier,Dakota Rogers,Judith N Mandl,Heather J Melichar

    Individual CD4+ T cells can become one of a number of helper (Th) lineages with distinct effector functions. However, whether biases in Th potential exist prior to antigen encounter is unknown. Studies have identified cell-intrinsic functional heterogeneity among naïve T cells that can be parsed based on the strength of T-cell receptor (TCR) interactions with self-peptide. Here, using CD5 levels as a surrogate for the strength of these basal TCR signals, we sought to identify pre-existing effector biases in the CD4+ T-cell lineage. We show that ex vivo-activated CD5lo CD4+ T cells produce greater amounts of the Th1 cytokine interferon-gamma (IFNγ) than their CD5hi counterparts. In addition, a greater percentage of CD5lo effector CD4+ T cells produce IFNγ in both polyclonal and monoclonal CD4+ T-cell populations after antigen challenge in vivo. These results suggest that differential IFNγ production potential exists among CD4+ T cells prior to activation and independent of TCR affinity for foreign antigen.

    更新日期:2019-11-01
  • Over-expression of p190RhoGEF enhances B-cell activation and germinal center formation in T-cell-dependent humoral immune responses.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-07-31
    Ji Hye Jeong,Yun Jung Ha,So-Yeon Choi,Jee-Hae Kim,Yungdae Yun,Jong Ran Lee

    Previously, we reported induced expression of the p190 Rho guanine nucleotide exchange factor (p190RhoGEF, ARHGEF28) following CD40 stimulation of B cells isolated from mouse spleen. We also reported that p190RhoGEF and a downstream effector molecule RhoA are required for B-cell differentiation, especially for the induction of the plasma cell (PC) differentiation. This study investigates the role of p190RhoGEF in B-cell biology in vivo, using p190RhoGEF transgenic (TG) mice that overexpress a wild-type full gene in B cells. Immunization of these mice with T-cell-dependent antigen showed that populations of germinal center B cells and PCs were significantly increased in TG mice. Furthermore, similar results were shown in recombination activating 1 (Rag1) knockout mice that were reconstituted with B cells isolated from TG mice in combination with T cells isolated from littermate control mice. Analyses of isotype class switching and transcription factors involved in a germinal center reaction and PC differentiation also supported the findings from the cellular responses. These results suggest that p190RhoGEF may play a role in the stage of PC differentiation during T-cell-dependent humoral immune responses.

    更新日期:2019-11-01
  • Chlamydia-infected macrophages are resistant to azithromycin treatment and are associated with chronic oviduct inflammation and hydrosalpinx development.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-07-28
    Marina Cg Harvie,Alison J Carey,Charles W Armitage,Connor P O'Meara,Jesse Peet,Zachary N Phillips,Peter Timms,Kenneth W Beagley

    Chlamydia infection remains the leading sexually-transmitted bacterial infection worldwide, causing damaging sequelae such as tubal scarring, infertility and ectopic pregnancy. As infection is often asymptomatic, prevention via vaccination is the optimal strategy for disease control. Vaccination strategies aimed at preventing bacterial infection have shown some promise, although these strategies often fail to prevent damaging inflammatory pathology when Chlamydia is encountered. Using a murine model of Chlamydia muridarum genital infection, we employed two established independent models to compare immune responses underpinning pathologic development of genital Chlamydia infection. Model one uses antibiotic treatment during infection, with only early treatment preventing pathology. Model two uses a plasmid-cured variant strain of C. muridarum that does not cause pathologic outcomes like the plasmid-containing wild-type counterpart. Using these infection models, contrasted by the development of pathology, we identified an unexpected role for macrophages. We observed that mice showing signs of pathology had greater numbers of activated macrophages present in the oviducts. This may have been due to early differences in macrophage activation and proinflammatory signaling leading to persistent or enhanced infection. These results provide valuable insight into the cellular mechanisms driving pathology in Chlamydia infection and contribute to the design and development of more effective vaccine strategies for protection against the deleterious sequelae of Chlamydia infection of the female reproductive tract.

    更新日期:2019-11-01
  • Daptomycin-resistant Staphylococcus aureus clinical isolates are poorly sensed by dendritic cells.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-09-29
    Timothy Patton,Jhih-Hang Jiang,Rachel J Lundie,Mariam Bafit,Wei Gao,Anton Y Peleg,Meredith O'Keeffe

    Methicillin-resistant Staphylococcus aureus (MRSA) presents an increasing threat to public health, with antimicrobial resistance on the rise and infections endemic in the hospital setting. Despite a global research effort to understand and combat antimicrobial resistance, less work has focused on understanding the nuances in the immunopathogenesis of clinical strains. In particular, there is a surprising gap of knowledge in the literature pertaining to how clinical strains are recognized by dendritic cells (DCs). Here, we show that the activation of DCs is compromised in response to MRSA strains resistant to the last-line antibiotic daptomycin. We found a significant reduction in the secretion of proinflammatory cytokines including tumor necrosis factor-α, interleukin-6, regulated upon activation, normal T cell expressed, and secreted and macrophage inflammatory protein-1β, as well as decreased expression of CD80 by DCs responding to daptomycin-resistant MRSA. We further demonstrate that this phenotype is coincident with the acquisition of specific point mutations in the cardiolipin synthase gene cls2, and, partly, in the bifunctional lysylphosphatidylglycerol flippase/synthetase gene mprF, which are genes that are often mutated in clinical daptomycin-resistant strains. Therefore, throughout infection and antibiotic therapy, MRSA has the capacity to not only develop further antibiotic resistance, but also develop resistance to immunological recognition by DCs, because of single amino acid point mutations occurring under the selective pressures of both host immunity and antibiotic therapy. Understanding the diversity of clinical MRSA isolates and the nuances in their immune recognition will have important implications for future therapeutics and the treatment of these infections.

    更新日期:2019-11-01
  • β-synuclein at the "synapse" of encephalitis and neurodegeneration in multiple sclerosis?
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-06-14
    Sarah A Richman,Christopher A Hunter

    Lodygin and colleagues recently identified a candidate grey matter target antigen in a rat model of multiple sclerosis, a disease classically associated with the white matter antigen, myelin.

    更新日期:2019-11-01
  • MARCH9-mediated ubiquitination regulates MHC I export from the TGN.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2017-06-01
    Francesca De Angelis Rigotti,Aude De Gassart,Carina Pforr,Florencia Cano,Prudence N'Guessan,Alexis Combes,Voahirana Camossetto,Paul J Lehner,Philippe Pierre,Evelina Gatti

    Given the heterogeneous nature of antigens, major histocompatibility complex class I (MHC I) intracellular transport intersects with multiple degradation pathways for efficient peptide loading and presentation to cytotoxic T cells. MHC I loading with peptides in the endoplasmic reticulum (ER) is a tightly regulated process, while post-ER intracellular transport is considered to occur by default, leading to peptide-bearing MHC I delivery to the plasma membrane. We show here that MHC I traffic is submitted to a previously uncharacterized sorting step at the trans Golgi network (TGN), dependent on the ubiquitination of its cytoplasmic tail lysine residues. MHC I ubiquitination is mediated by the E3 ligase membrane-associated RING-CH 9 (MARCH9) and allows MHC I access to Syntaxin 6-positive endosomal compartments. We further show that MARCH9 can also target the human MHC I-like lipid antigen-presentation molecule CD1a. MARCH9 expression is modulated by microbial pattern exposure in dendritic cells (DCs), thus revealing the role of this ubiquitin E3 ligase in coordinating MHC I access to endosomes and DC activation for efficient antigen cross-presentation.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Production of monoclonal antibodies against surface antigenic determinants of Klebsiella pneumoniae.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 1988-01-01
    J Uchiyama,Y Fujikura,H Kuniki,T Fukumoto,A Koshiro

    The production of four murine monoclonal antibodies (Kp26, Kp53, Kp62 and Kp71) to Klebsiella pneumoniae surface antigen(s) is described. The binding of all four monoclonal antibodies to K. pneumoniae was inhibited by F(ab')2 fragments of normal human serum IgG, suggesting that the antigenic determinants of K. pneumoniae detected by the four monoclonal antibodies may be similar to those recognized by human serum IgG. The antigen identified by Kp62 was purified from a deoxycholate-solubilized bacterial fraction using immunoaffinity chromatography. The molecular weight of the antigen was determined by sodium dodecyl sulphate polyacrylamide gel electrophoresis to be 50,000-70,000.

    更新日期:2019-11-01
  • Regulation of B-lineage cells by caspase 6.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2018-06-05
    Chie Watanabe,Geraldine L Shu,Natalia V Giltiay,Edward A Clark

    The caspase (Casp) family of proteases regulate both lymphocyte apoptosis and activation. Here, we show that Casp6 regulates early B-cell development. One-week-old Casp6 knockout (Casp6 KO) mice have significantly more splenic B-cell subsets than wild-type (WT) mice. Adult Casp6 KO mice have normal levels of total splenic B cells but have increased numbers of B1a B cells and CD43+ "transitional" or splenic red pulp (RP) B cells. These results suggested that Casp6 may function to control B-cell numbers under nonhomeostatic conditions and during B-cell development. Consistent with this model, reconstitution of B cells was dysregulated in Casp6 KO mice after sublethal irradiation. Furthermore, bone marrow pro-B, pre-B and immature B-cell numbers were significantly higher in 1-week-old Casp6 KO mice than in 1-week-old WT mice. Casp6 KO pro-B cells proliferated more in response to IL-7 than WT pro-B cells, suggesting that Casp6 regulates early B-cell responses to IL-7. Indeed, adult and aged Casp6 KO mice had elevated numbers of IL-7αR+ Sca1+ precursors of common lymphoid progenitors, suggesting Casp6 may help regulate progenitors of B cells and early B-lineage cells. Casp6 regulates B-cell programs both during early development and after antigen stimulation in the periphery.

    更新日期:2019-11-01
  • Pharmacological blockade of the CD39/CD73 pathway but not adenosine receptors augments disease in a humanized mouse model of graft-versus-host disease.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-04-09
    Nicholas J Geraghty,Debbie Watson,Ronald Sluyter

    Allogeneic hematopoietic stem cell transplantation is a curative therapy for a number of hematological malignancies, but is limited by the development of graft-versus-host disease (GVHD). CD39 and CD73 form an ectoenzymatic pathway that hydrolyzes extracellular adenosine 5'-triphosphate (ATP) to adenosine, which respectively exacerbate or alleviate disease in allogeneic mouse models of GVHD. The current study aimed to explore the role of the CD39/CD73 pathway and adenosine receptor (AR) blockade in a humanized mouse model of GVHD. Immunodeficient nonobese diabetic-severe combined immunodeficiency-IL-2 receptor γnull mice were injected with human peripheral blood mononuclear cells, and subsequently injected with the CD39/CD73 antagonist αβ-methylene-ADP (APCP) (50 mg kg-1 ) or saline for 7 days, or the AR antagonist caffeine (10 mg kg-1 ) or saline for 14 days. Mice predominantly engrafted human CD4+ and CD8+ T cells, with smaller proportions of human regulatory T cells, invariant natural killer T cells, monocytes and dendritic cells. Neither APCP nor caffeine altered engraftment of these human leukocyte subsets. APCP (CD39/CD73 blockade) augmented GVHD as shown through increased weight loss and worsened liver histology, including increased leukocyte and human T-cell infiltration, and increased apoptosis. This treatment also increased serum human IL-2 concentrations and decreased the frequency of human CD39- CD73- CD4+ T cells. In contrast, caffeine (AR blockade) did not alter GVHD severity or human serum cytokine concentrations (IL-2, IL-6, IL-10 or tumor necrosis factor-α). In conclusion, blockade of CD39/CD73 but not ARs augments disease in a humanized mouse model of GVHD. These results indicate that CD39/CD73 blockade maintains sufficient extracellular ATP concentrations to promote GVHD in this model.

    更新日期:2019-11-01
  • The peripheral differentiation of human natural killer T cells.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-03-16
    Jie Liu,Brenna J Hill,Sam Darko,Kaimei Song,Máire F Quigley,Tedi E Asher,Yohei Morita,Hui Y Greenaway,Vanessa Venturi,Daniel C Douek,Miles P Davenport,David A Price,Mario Roederer

    The peripheral maturation of human CD1d-restricted natural killer T (NKT) cells has not been well described. In this study, we identified four major subsets of NKT cells in adults, distinguished by the expression of CD4, CD8 and CCR5. Phenotypic analysis suggested a hierarchical pattern of differentiation, whereby immature CD4+ CD8- CCR5- cells progressed to an intermediate CD4+ CD8- CCR5+ stage, which remained less differentiated than the CD4- CD8- and CD4- CD8+ subsets, both of which expressed CCR5. This interpretation was supported by functional data, including clonogenic potential and cytokine secretion profiles, as well as T-cell receptor (TCR) excision circle analysis. Moreover, conventional and high-throughput sequencing of the corresponding TCR repertoires demonstrated significant clonotypic overlap within individuals, especially between the more differentiated CD4- CD8- and CD4- CD8+ subsets. Collectively, these results mapped a linear differentiation pathway across the post-thymic landscape of human CD1d-restricted NKT cells.

    更新日期:2019-11-01
  • The immunomodulatory effects of measles-mumps-rubella vaccination on persistence of heterologous vaccine responses.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-02-23
    Petra Zimmermann,Kirsten P Perrett,Fiona Rm van der Klis,Nigel Curtis

    It is proposed that measles-containing vaccines have immunomodulatory effects which include a reduction in all-cause childhood mortality. The antibody response to heterologous vaccines provides a means to explore these immunomodulatory effects. This is the first study to investigate the influence of measles-mumps-rubella (MMR) vaccine on the persistence of antibodies to a broad range of heterologous infant vaccinations given in the first year of life. In total, 319 children were included in the study. All infants received routine vaccinations at 6 weeks, 4 and 6 months of age. At 12 months of age, 212 children were vaccinated with MMR and Haemophilus influenzae type b-meningococcus C (Hib-MenC) vaccines while the remaining 99 children had not yet received these vaccines. In the MMR/Hib-MenC-vaccinated group, blood was taken 28 ± 14 days after receiving these vaccines. Antibodies against diphtheria, tetanus, pertussis [pertussis toxin (PT), filamentous hemagglutinin, pertactin], poliomyelitis (type 1, 2, 3) and 13 pneumococcal serotypes were measured. Seroprotection rates and geometric mean antibody concentrations were compared between MMR/MenC-Hib-vaccinated and MMR/MenC-Hib-naïve participants. In the final analysis, 311 children were included. Seroprotection rates were lower in MMR/Hib-MenC-vaccinated children against PT and pneumococcal serotype 19A. After adjustment for prespecified factors, MMR/Hib-MenC-vaccinated infants had significantly higher antibody concentrations against tetanus (likely explained by a boosting effect of the carrier protein, a tetanus toxoid), while for the other vaccine antigens there was no difference in antibody concentrations between the two groups. MMR vaccination given at 12 months of age in a developed country does not significantly influence antibody concentrations to heterologous vaccines received in the first year of life.

    更新日期:2019-11-01
  • Macrophage ERα promoted invasion of endometrial cancer cell by mTOR/KIF5B-mediated epithelial to mesenchymal transition.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-02-20
    Xuanxuan Jing,Jin Peng,Yu Dou,Jintang Sun,Chao Ma,Qingjie Wang,Lin Zhang,Xia Luo,Beihua Kong,Yun Zhang,Lijie Wang,Xun Qu

    Tumor-associated macrophages (TAMs) exert tumor-promoting effects. There have been reports that estrogen receptors (ERs) are expressed on the infiltrating macrophages of endometriosis, ovarian cancer and lung cancer. However, the role of ERs in macrophages is not well characterized. In this study, we identified that ER alpha (ERα) expression on the macrophages of human endometrial cancer was positively correlated with cancer progression. Conditioned medium from selective ERα agonist-treated M2 macrophages induced the epithelial to mesenchymal transition (EMT) in endometrial cancer cells. However, this effect can be inhibited by ERα antagonist. Here, we showed that macrophages ERα-engaged abundantly produced chemokine (C-C motif) ligand 18 (CCL18), and its expression promoted the invasion of endometrial cancer cells by activating the extracellular signal-regulated kinase 1/2 pathway, whereas suppressing CCL18 abrogated these effects. Furthermore, we identified that CCL18 derived from TAMs upregulated KIF5B expression to promote EMT via activating the PI3K/AKT/mTOR signaling pathway in endometrial cancer. Overall, our findings show how ERα-engaged infiltrating macrophages initiate chronic inflammation and promote the aggressive progression of endometrial cancer cells. ERα-positive TAMs act as drivers of endometrial cancer, which may become a potential therapeutic target.

    更新日期:2019-11-01
  • NLRC5 deficiency has a moderate impact on immunodominant CD8+ T-cell responses during rotavirus infection of adult mice.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-02-16
    Tian Sun,Richard L Ferrero,Stephen E Girardin,Jennifer L Gommerman,Dana J Philpott

    The NOD-like receptor (NLR) family plays an important role in innate immunity. Class II transactivator and NOD-like receptor caspase activation and recruitment domain CARD containing 5 (NLRC5) are unusual members of the NLR family that instead of recognizing pathogen-associated or damage-associated molecular patterns, form enhanceosomes with adaptor molecules and modulate major histocompatibility complex (MHC) class II and MHC class I expression, respectively. While NLRC5 has been shown to play a role during intracellular pathogen infection and tumor cell immune evasion, its role in regulating antigen-specific CD8+ T-cell responses at the intestinal mucosa has not been investigated. Here, we take advantage of the rotavirus model in adult mice to dissect the impact of NLRC5 on CD8+ T-cell responses to this viral infection at the gut mucosa. We show that while Nlrc5-/- mice exhibited normal proportions of T-cell subpopulations in the intraepithelial and lamina propria compartments, these mice had decreased baseline MHC class I expression on various immune cells in the lamina propria. Upon rotavirus infection, Nlrc5 deficiency resulted in impaired H2-Kb -restricted antigen-specific CD8+ T-cell responses, which were recapitulated in mice deficient for Nlrc5 within the dendritic cell compartment. The impaired CD8+ T-cell response in Nlrc5-/- mice was not significant enough to impact viral titers, suggesting compensation in Nlrc5-/- mice, perhaps as a result of higher numbers of activated B cells in the mesenteric lymph nodes and normal rotavirus-specific immunoglobulin A responses. Collectively, our results demonstrate a minor role for NLRC5 in modulating H2-Kb -restricted antigen-specific CD8+ T-cell responses in the small intestine during rotavirus infection in adult mice.

    更新日期:2019-11-01
  • Antibody opsonization enhances MAIT cell responsiveness to bacteria via a TNF-dependent mechanism.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-01-30
    Zoltán Bánki,Lisette Krabbendam,Dominik Klaver,Tianqi Leng,Simon Kruis,Hema Mehta,Brigitte Müllauer,Dorothea Orth-Höller,Heribert Stoiber,Christian B Willberg,Paul Klenerman

    Mucosal-associated invariant T (MAIT) cells are an abundant human T-cell subset with antimicrobial properties. They can respond to bacteria presented via antigen-presenting cells (APCs) such as macrophages, which present bacterially derived ligands from the riboflavin synthesis pathway on MR1. Moreover, MAIT cells are also highly responsive to cytokines which enhance and even substitute for T-cell receptor-mediated signaling. The mechanisms leading to an efficient presentation of bacteria to MAIT cells by APCs have not been fully elucidated. Here, we showed that the monocytic cell line THP-1 and B cells activated MAIT cells differentially in response to Escherichia coli. THP-1 cells were generally more potent in inducing IFNγ and IFNγ/TNF production by MAIT cells. Furthermore, THP-1, but not B, cells produced TNF upon bacterial stimulation, which in turn supported IFNγ production by MAIT cells. Finally, we addressed the role of antibody-dependent opsonization of bacteria in the activation of MAIT cells using in vitro models. We found that opsonization had a substantial impact on downstream MAIT cell activation by monocytes. This was associated with enhanced activation of monocytes and increased TNF release. Importantly, this TNF acted in concert with other cytokines to drive MAIT cell activation. These data indicate both a significant interaction between adaptive and innate immunity in the response to bacteria, and an important role for TNF in MAIT cell triggering.

    更新日期:2019-11-01
  • Modulating antibody-dependent cellular cytotoxicity of epidermal growth factor receptor-specific heavy-chain antibodies through hinge engineering.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2019-01-27
    Calvin D'Eall,Robert A Pon,Martin A Rossotti,Natalie Krahn,Maureen Spearman,Deborah Callaghan,Henk van Faassen,Greg Hussack,Jörg Stetefeld,Michael Butler,Yves Durocher,Jianbing Zhang,Kevin A Henry,Jamshid Tanha

    Human IgG1 and IgG3 antibodies (Abs) can mediate Ab-dependent cellular cytotoxicity (ADCC), and engineering of the Ab Fc (point mutation; defucosylation) has been shown to affect ADCC by modulating affinity for FcRγIIIa. In the absence of a CH 1 domain, many camelid heavy-chain Abs (HCAbs) naturally bear very long and flexible hinge regions connecting their VH H and CH 2 domains. To better understand the influence of hinge length and structure on HCAb ADCC, we produced a series of hinge-engineered epidermal growth factor receptor (EGFR)-specific chimeric camelid VH H-human Fc Abs and characterized their affinities for recombinant EGFR and FcRγIIIa, their binding to EGFR-positive tumor cells, and their ability to elicit ADCC. In the case of one chimeric HCAb (EG2-hFc), we found that variants bearing longer hinges (IgG3 or camelid hinge regions) showed dramatically improved ADCC in comparison with a variant bearing the human IgG1 hinge, in similar fashion to a variant with reduced CH 2 fucosylation. Conversely, an EG2-hFc variant bearing a truncated human IgG1 upper hinge region failed to elicit ADCC. However, there was no consistent association between hinge length and ADCC for four similarly engineered chimeric HCAbs directed against distinct EGFR epitopes. These findings demonstrate that the ADCC of some HCAbs can be modulated simply by varying the length of the Ab hinge. Although this effect appears to be heavily epitope-dependent, this strategy may be useful to consider during the design of VH H-based therapeutic Abs for cancer.

    更新日期:2019-11-01
  • Splenic hematopoietic stem cells display a pre-activated phenotype.
    Immunol. Cell Biol. (IF 3.947) Pub Date : 2018-03-12
    Emilie Coppin,Jonathan Florentin,Sathish Babu Vasamsetti,Anagha Arunkumar,John Sembrat,Mauricio Rojas,Partha Dutta

    Splenic hematopoiesis is crucial to the pathogenesis of diseases including myocardial infarction and atherosclerosis. The spleen acts as a reservoir of myeloid cells, which are quickly expelled out in response to acute inflammation. In contrast to the well-defined bone marrow hematopoiesis, the cellular and molecular components sustaining splenic hematopoiesis are poorly understood. Surprisingly, we found that, unlike quiescent bone marrow hematopoietic stem cells (HSC), most of splenic HSC are in the G1 phase in C57BL/6 mice. Moreover, splenic HSC were enriched for genes involved in G0-G1 transition and expressed lower levels of genes responsible for G1-S transition. These data indicate that, at steady state, splenic HSC are pre-activated, which may expedite their cell cycle entry in emergency conditions. Consistently, in the acute phase of septic shock induced by LPS injection, splenic HSC entered the S-G2-M phase, whereas bone marrow HSC did not. Mobilization and transplantation experiments displayed that bone marrow HSC, once in the spleen, acquired cell cycle status similar to splenic HSC, strongly suggesting that the splenic microenvironment plays an important role in HSC pre-activation. In addition, we found that myeloid translocation gene 16 (Mtg16) deficiency in C57BL/6 mice resulted in significantly increased S-G2-M entry of splenic but not bone marrow HSC, suggesting that Mtg16 is an intrinsic negative regulator of G1-S transition in splenic HSC. Altogether, this study demonstrates that compared to bone marrow, splenic HSC are in a pre-activated state, which is driven by extracellular signals provided by splenic microenvironment and HSC intrinsic factor Mtg16.

    更新日期:2019-11-01
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