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  • Ex vivo expansion of regulatory T cells from long-term Belatacept-treated kidney transplant patients restores their phenotype and suppressive function but not their FOXP3 TSDR demethylation status
    Cell. Immunol. (IF 3.291) Pub Date : 2020-01-14
    A. Cortés-Hernández; E. Alvarez-Salazar; S. Arteaga-Cruz; J. Alberú Gómez; G. Soldevila

    We recently reported that Tregs from long-term Belatacept-treated kidney transplant patients displayed an altered phenotype and impaired suppressive function compared to Tregs from healthy controls. However, it remains unknown whether ex vivo expansion of Tregs from patients who underwent long-term immunosuppression may be feasible to be used in their treatment. In this work, Tregs from Belatacept-treated patients were polyclonally expanded in vitro in the presence of rapamycin and IL-2. After four weeks of expansion, Tregs from patients expressed high levels of FOXP3, CD25, CTLA-4, Helios and CCR7, and showed strong suppressive activity, even in the presence of pro-inflammatory cytokines. However, FOXP3 TSDR demethylation remained lower in expanded Tregs from Belatacept-treated patients compared to healthy control Tregs. These data suggest that ex vivo expansion of Tregs from patients undergoing long-term immunosuppression may require the use of epigenetic modifying agents to stabilize FOXP3 expression to be considered as treatment in kidney transplant patients.

    更新日期:2020-01-14
  • Oncolytic adenovirus targeting TGF-β enhances anti-tumor responses of mesothelin-targeted chimeric antigen receptor T cell therapy against breast cancer
    Cell. Immunol. (IF 3.291) Pub Date : 2020-01-11
    Yuxiang Li; Fengjun Xiao; Aimei Zhang Resource; Dan Zhang; Wenbo Nie; Tianxin Xu; Bing Han; Prem Seth; Hua Wang; Yuefeng Yang; Lisheng Wang

    Chimeric antigen receptor (CAR)-modified T cell therapy evokes only modest antitumor responses in solid tumors. Meso-CAR-T cells are CAR-T cells targeted mesothelin, which are over-expressed in tumor tissues of breast cancer patients. To improve the therapeutic effects, we combined it with rAd.sT, a transforming growth factor β signaling-targeted oncolytic adenovirus, to therapy breast cancer. In subcutaneous MDA-MB-231 xenograft of NSG mice, both rAd.sT and meso-CAR-T inhibited tumor growth, however combination therapy produced stronger inhibitory effects. Interestingly, rAd.sT reduced tumor burden at initial stage following vector treatments, while meso-CAR-T cells decreased tumor burden at a later stage. Moreover, meso-CAR-T could target tumor microenvironments, and combination therapy could enhance cytokines production, such as interleukin (IL)-6 and IL-12 in tumor microenvironment. In conclusion, combination of rAd.sT with meso-CAR-T produced much more impressive antitumor responses to breast cancer and its metastasis, which could be developed as a promising therapeutic strategy.

    更新日期:2020-01-13
  • Role of tissue plasminogen activator in clinical aggravation of experimental autoimmune encephalomyelitis and its therapeutic potential
    Cell. Immunol. (IF 3.291) Pub Date : 2020-01-10
    Tehila Mizrachi; Devorah Gur-Wahnon; Abd Al-Roof Higazi; Talma Brenner

    Tissue plasminogen activator (tPA), a component of the plasminogen activator (PA) system, is elevated in inflammatory neurological disorders. In the present study, we explored the immunomodulatory activity of tPA in experimental autoimmune encephalomyelitis (EAE). The EAE was treated with two catalytic inactive tPA variant proteins: S(481)A and S(481)A+KHRR(296−299)AAAA. EAE-induced tPA-/- mice presented with markedly more severe disease than wt EAE mice. Further, treatment with tPA variants, demonstrated a significant suppression of disease severity in tPA-/- and wt mice. Immunological evaluation showed that specific T-cell reactivity was markedly reduced in the tPA-/- animals, as indicated by decreased T-cell reactivity and reduction in T-regulatory cells. The current findings indicate that tPA plays a role in the pathogenesis of EAE. Moreover, successful amelioration of EAE was achieved by administration of tPA variant proteins. This might mean that these proteins have potential for the immunomodulation of neuroinflammation.

    更新日期:2020-01-11
  • Application of molecular imaging technology in tumor immunotherapy
    Cell. Immunol. (IF 3.291) Pub Date : 2020-01-08
    Yiming Meng; Jing Sun; Na Qv; Guirong Zhang; Tao Yu; Haozhe Piao
    更新日期:2020-01-09
  • Similarities and differences in the effects of sensitisation and challenge with Dermatophagoides farinae and Dermatophagoides pteronyssinus extracts in a murine asthma surrogate
    Cell. Immunol. (IF 3.291) Pub Date : 2020-01-08
    Wenjun Wang; Gao An; Yan Li; Chris J Corrigan; Wei Wang; Sun Ying; Kewu Huang

    Patients with atopic asthma may become sensitised to the grain storage mite Dermatophagoides farinae (Der f), the house dust mite Dermatophagoides pteronyssinus (Der p) or both, but thus far little attention has been paid to date to possible variation in their pathophysiological effects. Here we present a side by side comparison of the effects of extracts of these two dust mites in a murine surrogate of atopic asthma. Compared with the Der p-challenged mice, however, the mice-challenged with Der f had favour changes in lung tissue elasticity and expression in matrix metalloproteinases in lung tissue, while the mice challenged with Der p showed more neutrophils infiltrating around the airway and stronger expression of steroid-resistant related cytokines in the lung tissue. Our data suggest that different dust mite crude extracts might lead different pathological characteristics, at least in murine models of asthma.

    更新日期:2020-01-09
  • Synergistic effect of adoptive immunotherapy and docetaxel inhibits tumor growth in a mouse model
    Cell. Immunol. (IF 3.291) Pub Date : 2019-12-31
    Yuefeng Hu; Jingwei Liu; Peilin Cui; Tao Liu; Chunmei Piao; Xianghong Xu; Qike Zhang; Man Xiao; Yongcheng Lu; Xuesong Liu; Yue Wang; Xu Lu

    Adoptive T cell transfer therapy (ACT) has emerged as a promising approach to cancer immunotherapy; however, the efficacy of ACT is limited by the T-cell suppressive activity of myeloid-derived suppressor cells (MDSCs), which accumulate in the tumor microenvironment after ACT. We sought to determine whether the efficacy of ACT could be enhanced by co-treatment with docetaxel, a taxane chemotherapy agent that has been shown previously to inhibit MDSC function. Using a mouse tumor model, we demonstrated that ACT and docetaxel synergistically inhibit the growth either of engrafted CT26 colon cancer or 4T1 mammary carcinoma cells. While ACT mediated an increase in the recruitment of MDSCs to the site of the tumor, docetaxel reversed this increase. Furthermore, ex vivo cultures of tumor-associated MDSCs suppressed the cytotoxic activity of tumor-specific T cells, and this suppressive activity was abolished by docetaxel treatment. These results suggest that docetaxel inhibits both the tumor recruitment and T cell suppressive activity of MDSCs. Inhibitors of iNOS and arginase partially inhibited ex vivo MDSC activity, and combined inhibition of iNOS and arginase had a similar effect as docetaxel, which supports the possibility that docetaxel may function by inhibiting ACT-associated activation of these pathways. Furthermore, docetaxel mediated inhibition of the T cell suppressive activity of MDSCs from human blood, which supports the potential clinical applicability of these findings. On the basis of these findings, docetaxel treatment may represent an effective therapeutic approach for reversing immunosuppression by MDSCs subsequent to ACT-based therapy.

    更新日期:2019-12-31
  • Piper Nigrum extract improves OVA-induced nasal epithelial barrier dysfunction via activating Nrf2/HO-1 signaling
    Cell. Immunol. (IF 3.291) Pub Date : 2019-12-30
    Thi Tho Bui; Chun Hua Piao; Eunjin Hyeon; Yanjing Fan; Chang Ho Song; Hee Soon Shin; Ok Hee Chai

    Background Piper nigrum L. (Piperaceae) is commonly used as a spice and traditional medicine in many countries. It has been reported to have anti-oxidant, anti-bacterial, anti-tumor, anti-mutagenic, anti-diabetic, and anti-inflammatory properties. However, the protective role of P. nigrum on upper respiratory tract injury in an allergic rhinitis (AR) mouse model has been unclear. This study aims to investigate the anti-allergic, anti-inflammation effects of P. nigrum fruit extract (PNE) on the upper respiratory tract in an ovalbumin (OVA)-induced AR model. Methods AR mouse model was established by intraperitoneal injection with 200 µl saline containing 50 µg OVA adsorbed to 1 mg aluminum hydroxide, and intranasal challenge with 20 µl per nostril of 1 mg/ml OVA. Besides, mice were orally administrated once daily with PNE and dexamethasone (Dex) in 13 days. The nasal symptoms, inflammatory cells, OVA-specific immunoglobulins, cytokines, nasal histopathology, and immunohistochemistry were evaluated. Results The PNE oral administrations inhibited allergic responses via reduction of OVA-specific antibodies levels and mast cells histamine release, accordingly, the nasal symptoms in the early-phase reaction were also clearly ameliorated. In both nasal lavage fluid and nasal tissue, PNE suppressed the inflammatory cells accumulation, specifically with eosinophils. The intravenous Evans blue injection illustrated the permeability reduction of nasal mucosa layer in PNE-treated mice. Also; PNE treatments protected the epithelium integrity by preventing the epithelial shedding from nasal mucosa; as a result of enhancing the strong expression of the E-cadherin tight junction protein in cell-to-cell junctions, as well as inhibiting the degraded levels of zonula occludens-1 (ZO-1) and occludin into the nasal cavity. Additionally, PNE protected against nasal epithelial barrier dysfunction via enhancing the expression of Nrf2 activated form which led to increasing synthesis of the anti-inflammation enzyme HO-1. Conclusions These obtained results suggest that PNE has a promising strategy for immunotherapy in allergic rhinitis treatment.

    更新日期:2019-12-30
  • PKC signaling contributes to chromatin decondensation and is required for competence to respond to IL-2 during T cell activation
    Cell. Immunol. (IF 3.291) Pub Date : 2019-12-11
    Jennifer R. Funsten, Keny O. Murillo Brizuela, Hayley E. Swatzel, Audrey S. Ward, Tia A. Scott, Sarah M. Eikenbusch, Molly C. Shields, Jenna L. Meredith, Taylor Y. Mitchell, Megan L. Hanna, Kellie N. Bingham, Jason S. Rawlings
    更新日期:2019-12-11
  • Epigenetic and transcriptional analysis supports human regulatory T cell commitment at the CD4+CD8+ thymocyte stage
    Cell. Immunol. (IF 3.291) Pub Date : 2019-12-11
    Reetta Vanhanen, Katarzyna Leskinen, Ilkka P. Mattila, Päivi Saavalainen, T. Petteri Arstila

    The natural CD25+ FOXP3+ regulatory T cell (Treg) population is generated as a distinct lineage in the thymus, but the details of Treg development in humans remain unclear, and the timing of Treg commitment is also contested. Here we have analyzed the emergence of CD25+ cells at the CD4+CD8+ double positive (DP) stage in the human thymus. We show that these cells share T cell receptor repertoire with CD25+ CD4 single-positive thymocytes, believed to be committed Tregs. They already have a fully demethylated FOXP3 enhancer region and thus display stable expression of FOXP3 and the associated Treg phenotype. Transcriptome analysis also grouped the DP CD25+ and CD4 CD25+ thymocytes apart from the CD25- subsets. Together with earlier studies, our data are consistent with human Treg commitment already at the DP thymocyte stage. We suggest that the most important antigens and signals necessary for human Treg differentiation may be found in the thymic cortex.

    更新日期:2019-12-11
  • PGE2 ameliorated viral myocarditis development and promoted IL-10-producing regulatory B cell expansion via MAPKs/AKT-AP1 axis or AhR signaling
    Cell. Immunol. (IF 3.291) Pub Date : 2019-12-06
    Rong Chen, Yuwen Cao, Yu Tian, Yufeng Gu, Hongxiang Lu, Shiqing Zhang, Huaxi Xu, Zhaoliang Su

    B10 cells, a specific subset of regulatory B cells, are capable of regulating immune response and restricting inflammation and autoimmune disease progression by producing IL-10. B10 cells frequently change significantly during inflammation and autoimmunity. However, how B10 cell populations change in viral myocarditis (VMC) remains unclear. Therefore, this work was conducted to clarify the changes in B10 cells and their potential mechanisms. Our results showed that the B10 cell frequency significantly changed in the VMC model. Changes in prostaglandin E2 (PGE2) levels in VMC model hearts were consistent with B10 expansion. PGE2 induced B10 cell expansion via the MAPKs/AKT-AP1 axis or AhR signaling. Additionally, PGE2-pretreated B10 cells inhibited naïve CD4+ T cell differentiation into Th17 cells. In vivo, PGE2 treatment or adoptive B10 cell transfer significantly restricted VMC development. Our results provide sufficient evidence that PGE2-induced B10 cell expansion may become a promising therapeutic approach for VMC and acute inflammatory injury.

    更新日期:2019-12-07
  • C-kit-derived CD11b+ Cells are Critical for Cardiac Allograft Prolongation by Autologous C-kit+ Progenitor Cells
    Cell. Immunol. (IF 3.291) Pub Date : 2019-12-02
    R.J. Plenter, M.G. Coulombe, H.M. Roybal, C.M. Lin, R.G. Gill, M.R. Zamora, T.J. Grazia

    Autologous C-kit+ cells robustly prolong cardiac allografts. As C-kit+ cells can transdifferentiate to hematopoietic cells as well as non-hematopoietic cells, we aimed to clarify the class(es) of C-kit-derived cell(s) required for cardiac allograft prolongation. Autologous C-kit+ cells were administered post-cardiac transplantation and allografts were evaluated for C-kit+ inoculum-derived cells. Results suggested that alloimmunity was a major signal for trafficking of C-kit-derived cells to the allograft and demonstrated that C-kit+ inoculum-derived cells expressed CD11b early after transfer. Allograft survival studies with CD11b-DTR C-kit+ cells demonstrated a requirement for C-kit+-derived CD11b+ cells. Co-therapy studies demonstrated near complete abrogation of acute rejection with concomitant CTLA4-Ig therapy and no loss of prolongation in combination with Cyclosporine A. These results strongly implicate a C-kit-derived myeloid population as critical for allograft preservation and demonstrate the potential therapeutic application of autologous C-kit+ progenitor cells as calcineurin inhibitor-sparing agents and possibly as co-therapeutics for durable graft survival.

    更新日期:2019-12-02
  • Aging, sex, inflammation, frailty, and CMV and HIV Infections
    Cell. Immunol. (IF 3.291) Pub Date : 2019-11-27
    Sean X Leng, Joseph B Margolick

    Aging is characterized by significant immune remodeling at both cellular and molecular levels, also known as immunosenescence. Older adults often manifest a chronic low-grade inflammatory phenotype. These age-related immune system changes have increasingly been recognized not only to lead to immune functional decline and increased vulnerability to infections, but also to play an important role in many chronic conditions such as frailty in older adults. In addition to sex as an important biological factor, chronic viral infections including that by human immunodeficiency virus (HIV) and cytomegalovirus (CMV) are all known to have major impact on the aging immune system. This article provides an overview of our current understanding of aging immunity, sex, inflammation, frailty, and HIV and CMV infections.

    更新日期:2019-11-28
  • Proteomics analysis reveals the interleukin-35-dependent regulatory mechanisms affecting CD8+ T-cell functions
    Cell. Immunol. (IF 3.291) Pub Date : 2019-11-26
    Xuefen Li, Yuejiao Dong, Kexin Tu, Weilin Wang

    Interleukin (IL)-35 strongly suppresses the immune effects of CD8+ T cells. However, the mechanisms mediating these effects are not clear. Here, we investigated the potential inhibitory mechanisms of IL-35 using proteomics technology. The changes of differentially expressed proteins (DEPs) were evaluated using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. IL-35 negatively regulated the expression of proteins in the biological processes category. GO analysis identified cellular immunosuppression regulation and external stimulation of regulatory proteins as pathways that were most affected by IL-35. Among the proteins regulated in these pathways, cell-matrix adhesion junction and anchoring junction proteins were more abundant. KEGG pathway analysis showed that cytochrome c and IL-12A were significantly altered. DEPs were related to cell signaling, migration, inhibition, apoptosis, and enrichment of arachidonic acid metabolism. These findings improved our understanding of the roles of IL-35 in inhibition of CD8+ T cells.

    更新日期:2019-11-27
  • Analysis of macrophages and neutrophils infiltrating murine mammary carcinoma sites within hours of tumor delivery
    Cell. Immunol. (IF 3.291) Pub Date : 2019-06-04
    Chenyu Zhang, Matthew Adusei, Alison Baranovic, Matthew DeBenedetto, Amanda Lauricella, Silvia Chilel Martin, Catherine Newsom-Stewart, Jennifer Schwartz, Robert A. Kurt

    Here we used three different murine mammary carcinomas to study the immune environment associated with early tumor sites. While it was not surprising that the early immune response was predominated by macrophages and neutrophils, there were some novel findings at this early stage of disease. For instance, the macrophages and neutrophils expressed a mixed cytokine profile with TNF-α and TGF-β both produced at appreciable levels. Moreover, while the cells retained their phagocytic capacity, production of reactive oxygen species by the macrophages and neutrophils was in decline. Alterations in the metabolic profile of the tumor associated macrophages were also evident with a decrease in the ATP production rate, and a higher dependence on oxidative phosphorylation for ATP production. Collectively, these data indicate a mixed phenotype of tumor-associated macrophages and neutrophils evident within hours of murine mammary carcinoma delivery.

    更新日期:2019-11-18
  • Recurrence of Disease Following Organ Transplantation in Autoimmune Liver Disease and Systemic Lupus Erythematosus
    Cell. Immunol. (IF 3.291) Pub Date : 2019-11-16
    Atsushi Tanaka, Hajime Kono, Patrick S.C. Leung, M. Eric Gershwin

    Disease recurrence after organ transplantation associated with graft failure is a major clinical challenge in autoimmune diseases. Primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and autoimmune Hepatitis (AIH) are the three most common (autoimmune liver diseases) ALD for which liver transplantation (LT) is the most effective treatment option for patients with end-stage diseases. Although the 5- and 10-year survival rates of post-LT patients are remarkable (80-84% and 71-79% in PBC, 73-87% and 58-83% in PSC, 76%-79% and 67%-77% respectively in AIH patients), post-LT disease recurrence is not uncommon. Here, we summarize literature findings on disease recurrence of these ALD with emphasis on the incidence, risk factors and impact on long-term outcome. We noted that the incidence of disease recurrence varies between studies, which ranges from 53% to 10.9% in PBC, 8.2% to 44.7 % in PSC and 7% to 42% in AIH. The variations are likely due to differences in study design, such as sample size, duration of studies and follow up time. This is further compounded by the lack of precise clinical diagnosis criteria and biomarkers of disease recurrence in these ALD, variation in post-LT treatment protocols to prevent disease recurrence and a multitude of risk factors associated with these ALD. While recurrence of PBC and AIH does not significantly impact long term outcome including overall survival, recurrent PSC patients often require another LT. Renal transplantation, like LT, is the treatment of choice in patients with end-stage lupus nephritis. While calcineurin inhibitor (CNI) and immunosuppressive drugs have improved the survival rate, post-transplant recurrence of lupus nephritis from surveillance-biopsy proven lupus nephritis range from 30% to 44%. On the other hand, recurrence of post-transplant lupus nephritis from registry survey analysis were only 1.1% to 2.4% . In general, risk factors associated with an increased frequency of post-transplant recurrence of autoimmune diseases are not clearly defined. Large scale multi-center studies are needed to further define guidelines for the diagnosis and clinical management to minimize disease recurrence and improve outcomes of post-transplant patients.

    更新日期:2019-11-18
  • Imaging: Gear up for mechano-immunology
    Cell. Immunol. (IF 3.291) Pub Date : 2019-05-16
    Zhengpeng Wan, Samina Shaheen, Alicia Chau, Yingyue Zeng, Wanli Liu

    Immune cells including B and T lymphocytes have a remarkable ability to sense the physical perturbations through their surface expressed receptors. At the advent of modern imaging technologies paired with biophysical methods, we have gained the understanding of mechanical forces exerted by immune cells to perform their functions. This review will go over the imaging techniques already being used to study mechanical forces in immune cells. We will also discuss the dire need for new modern technologies for future work.

    更新日期:2019-11-18
  • Intravital imaging of skin infections
    Cell. Immunol. (IF 3.291) Pub Date : 2019-04-01
    Ali Zaid

    Intravital imaging of cutaneous immune responses has revealed intricate links between the skin’s structural properties, the immune cells that reside therein, and the carefully orchestrated migratory dynamics that enable rapid sensing and subsequent elimination of skin pathogens. In particular, the development of 2-photon intravital microscopy (2P-IVM), which enables the excitation of fluorescent molecules within deep tissue with minimal light scattering and tissue damage, has proven an invaluable tool in the characterization of different cell subset’s roles in skin infection. The ability to visualize cells, tissue structures, pathogens and track migratory dynamics at designated times following infection, or during inflammatory responses has been crucial in defining how immune responses in the skin are coordinated, either locally or in concert with circulating immune cells. Skin pathogens affect millions of people worldwide, and skin infections leading to cutaneous pathology have a considerable impact on the quality of life and longevity of people affected. In contrast, pathogens that infect the skin to later cause systemic illness, such as malaria parasites and a variety of arthropod-borne viruses, or infection in distant anatomical sites are a significant cause of morbidity and mortality worldwide. Here, we review recent advances and seminal studies that employed intravital imaging to characterize key immune response mechanisms in the context of viral, bacterial and parasitic skin infections, and provide insights on skin pathogens of global significance that would benefit from such investigative approaches.

    更新日期:2019-11-18
  • Imaging the neutrophil: Intravital microscopy provides a dynamic view of neutrophil functions in host immunity
    Cell. Immunol. (IF 3.291) Pub Date : 2019-01-23
    Andrew O. Yam, Tatyana Chtanova

    Neutrophils are the first cellular responders of the immune system. They employ their impressive arsenal of microbicidal molecules to provide rapid and efficient defense against pathogens. However, the role of neutrophils extends far beyond microbial destruction to include tissue repair and remodeling, provision of signals to the adaptive immune system and body homeostasis. Intravital imaging has allowed the visualization of neutrophils in their native environment in both health and disease and provided crucial insights into their mechanisms of action. In the last few years the power of intravital imaging has been considerably extended by the introduction of photoconvertible proteins and intracellular signaling reporter mice. This review will highlight recent advances in our understanding of neutrophil biology based on the use of intravital microscopy to visualize their modus operandi in vivo including migration in and out of inflamed tissues, host-pathogen interactions and cell fate.

    更新日期:2019-11-18
  • Live imaging of the pulmonary immune environment
    Cell. Immunol. (IF 3.291) Pub Date : 2018-10-09
    Mark R. Looney, Mark B. Headley

    The lung represents a unique immune environment. The primary function of the lung is to enable gas exchange by facilitating the transfer of oxygen into and carbon dioxide out of the blood. However, as a direct byproduct of this process the lung is also constantly exposed to particles, allergens, and pathogens alongside air itself. Due to this, the pulmonary immune system exists in a fine balance between quiescence and inflammation, deviations from which can lead to a failure in respiratory function. A rich history exists attempting to define the critical features of lung immunity, and most recently advances in intravital microscopy have enabled the visualization of intercellular immune dynamics in both steady-state and a variety of disease conditions. In this review, we will summarize a variety of approaches to intravital lung imaging as well as how its application has advanced our understanding of normal lung function as well as disease states such as pulmonary metastasis, asthma, and lung injury.

    更新日期:2019-11-18
  • Visualizing immune responses of the airway mucosa
    Cell. Immunol. (IF 3.291) Pub Date : 2018-10-03
    Tibor Z. Veres

    The airway mucosa is the primary tissue site exposed to inhaled particulate matter, which includes pathogens and allergens. While most inhaled particles are eliminated from the airways via mucociliary clearance, some pathogens may penetrate the mucosal epithelial barrier and an effective activation of the mucosal immune system is required to prevent further pathogen spread. Similarly, inhaled environmental allergens may induce an aberrant activation of immune cells in the airway mucosa, causing allergic airway disease. During the last years, several investigators employed advanced microscopic imaging on both intravital and tissue explant preparations to observe the dynamic behavior of various immune cells within their complex tissue environment. In the respiratory tract, most imaging studies focused on immune responses of the alveolar compartment in the lung periphery. However, equally important immunological events occur more proximally in the mucosa of the conducting airways, both during infection and allergic responses, calling for a more detailed imaging analysis also at this site. In this review, I will outline the technical challenges of designing microscopic imaging experiments in the conducting airways and summarize our recent efforts in understanding airway mucosal immune cell dynamics in steady–state conditions, during infection and allergy.

    更新日期:2019-11-18
  • Intravital imaging of cutaneous immune responses
    Cell. Immunol. (IF 3.291) Pub Date : 2018-05-26
    Satoshi Nakamizo, Gyohei Egawa, Kahbing Jasmine Tan, Kenji Kabashima

    Various immune cells are present in the skin and modulate the cutaneous immune response. In order to capture such dynamic phenomena, intravital imaging is an important technique and there is a possibility to provide substantial information that is not available using conventional histological analysis. Multiphoton microscope enable direct, three-dimensional, minimally invasive imaging of biological samples with high spatiotemporal resolution, and now become the main method for intravital imaging studies. Here, we will introduce the latest knowledge obtained by intravital imaging of the skin.

    更新日期:2019-11-18
  • Emergence of antibodies endowed with proteolytic activity against High-mobility group box 1 protein (HMGB1) in patients surviving septic shock
    Cell. Immunol. (IF 3.291) Pub Date : 2019-11-15
    Stéphanie Barnay-Verdier, Chloé Borde, Lakhdar Fattoum, Bharath Wootla, Sébastien Lacroix-Desmazes, Srini Kaveri, Sébastien Gibot, Vincent Maréchal

    High-mobility group box 1 (HMGB1) concentration in serum or plasma has been proposed as an important biological marker in various inflammation-related pathologies. We previously showed that low titer autoantibodies against HMGB1 could emerge during the course of sepsis. Importantly their presence was positively related with patients’ survival. In this study, we focused on plasma samples from 2 patients who survived sepsis and exhibited high titer antibodies to HMGB1. These antibodies were proved to be specific for HMGB1 since they did not bind to HMGB2 or to human serum albumin. Following IgG purification, it has shown that both patients secreted HMGB1-hydrolyzing autoantibodies in vitro. These findings suggested that proteolytic antibodies directed against HMGB1 can be produced in patients surviving septic shock.

    更新日期:2019-11-15
  • Multi-Gene Technical Assessment of qPCR and Nanostring n-Counter Analysis Platforms in Cynomolgus Monkey Cardiac Allograft Recipients
    Cell. Immunol. (IF 3.291) Pub Date : 2019-11-08
    Emily A.S. Bergbower, Richard N. Pierson, Agnes M. Azimzadeh

    Quantitative gene expression profiling of cardiac allografts characterizes the phenotype of the alloimmune response, yields information regarding differential effects that may be associated with various anti-rejection drug regimens, and generates testable hypotheses regarding the pathogenesis of the chronic rejection lesions typically observed in non-human primate heart transplant models. The goal of this study was to assess interplatform performance and variability between the relatively novel NanoString nCounter Analysis System, ΔΔCT (relative) RT-qPCR, and standard curve (absolute) RT-qPCR utilizing cynomolgus monkey cardiac allografts. Methods for RNA isolation and preamplification were also systematically evaluated and effective methods are proposed. In this study, we demonstrate strong correlation between the two RT-qPCR methods, but variable and, at times, weak correlation between RT-qPCR and NanoString. NanoString fold change results demonstrate less sensitivity to small changes in gene expression than RT-qPCR. These findings appear to be driven by technical aspects of each platform that influence the conditions under which each technique is ideal. Collectively, our data contribute to the general effort to optimally utilize gene expression profiling techniques, not only for transplanted tissues, but for many other applications where accurate rank-order of gene expression versus precise quantification of absolute gene transcript number may be relatively valuable.

    更新日期:2019-11-08
  • B7-H4, a promising target for immunotherapy
    Cell. Immunol. (IF 3.291) Pub Date : 2019-11-04
    Jia-Yu Wang, Wei-Peng Wang

    The coinhibitory molecule B7-H4, an important member of the B7 family, is abnormally expressed in tumors, inflammation and autoimmune diseases. B7-H4 negatively regulates T cell immune response and promotes immune escape by inhibiting the proliferation, cytokine secretion, and cell cycle of T cells. Moreover, B7-H4 plays an extremely important role in tumorigenesis and tumor development including cell proliferation, invasion, metastasis, anti-apoptosis, etc. In addition, B7-H4 has the other biological functions, such as protection against type 1 diabetes (T1D) and islet cell transplantation. Therefore, B7-H4 has been identified as a novel marker or a therapeutic target for the treatment of tumors, inflammation, autoimmune diseases, and organ transplantation. Here, we summarized the expression profiles, physiological and pathological functions, and regulatory mechanisms of B7-H4, the signaling pathways involved, as well as B7-H4-based immunotherapy.

    更新日期:2019-11-04
  • 更新日期:2019-11-04
  • Aging and Influenza Vaccine-Induced Immunity
    Cell. Immunol. (IF 3.291) Pub Date : 2019-10-31
    Haley L. Dugan, Carole Henry, Patrick C. Wilson

    Immunosenescence is defined as the progressive deterioration of the immune system with aging. Immunosenescence stifles the generation of protective B and T cell-mediated adaptive immunity in response to various pathogens, resulting in increased disease susceptibility and severity in the elderly population. In particular, immunosenescence has major impacts on the phenotype, function, and receptor repertoire of B and T cells in the elderly, hindering protective responses induced by seasonal influenza virus vaccination. In order to overcome the detrimental impacts of immunosenescence on protective immunity to influenza viruses, we review our current understanding of the effects of aging on adaptive immune responses to influenza and discuss current and future avenues of vaccine research for eliciting more potent anti-influenza immunity in the elderly.

    更新日期:2019-11-01
  • NHP-Immunome: A translational research-oriented database of non-human primate immune system proteins
    Cell. Immunol. (IF 3.291) Pub Date : 2019-10-31
    David F. Plaza, Manuel F. Gómez, Manuel A. Patarroyo

    We are currently living the advent of a new age for medicine in which basic research is being quickly translated into marketable drugs, and the widespread access to genomics data is allowing the design and implementation of personalized solutions to medical conditions. Non-human primates (NHP) have gained an essential role in drug discovery and safety testing due to their close phylogenetic relationship to humans. In this study, a collection of well characterized genes of the human immune system was used to define the orthology-based immunome in four NHP species, with carefully curated annotations available based on multi-tissue RNA-seq datasets. A broad variation in the frequency of expressed protein isoforms was observed between species. Finally, this analysis also revealed the lack of expression of at least four different chemokines in new-world primates. In addition, transcripts corresponding to four genes including interleukin 12 subunit alpha were expressed in humans but no other primate species analyzed. Access to the non-human primate immunome is available in http://www.fidic.org.co:90/proyecto/.

    更新日期:2019-11-01
  • The participation of sialic acids in microglia-neuron interactions.
    Cell. Immunol. (IF 3.291) Pub Date : 2012-01-03
    Przemyslaw Wielgat,Jan J Braszko

    Since it is known that sialic acid participates in neuronal plasticity, it is resonable to investigate its role in microglia-neuron interactions. In this study, we tested the effects of enzymatic removal of sialic acid on neurite and cell body density in microglia-neuron co-cultures. Additionaly, we analyzed the expression of Siglec-F protein, putative receptor for sialic acids, in microglial cells as well as its affinity to neurons. The results showed that removal of sialic acids affects neuronal integrity and changes microglial morphology. In presence of microglial cells, endoneuraminidase and α-neuraminidase significantly reduced neurite density (p<0.05). Endoneuraminidase (p<0.05) and α-neuraminidase (p>0.05) decreased the number of neuronal cell bodies in comparison to control co-cultures. Neuraminidases-treated neurons showed reduced binding of Siglec-F protein, which we found in microglial cells. Our results suggest that interactions between sialic acids and Siglec receptors may protect neuronal integrity during neurodegenerative processes.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Sex differences in regulatory cells in experimental stroke.
    Cell. Immunol. (IF 3.291) Pub Date : 2017-06-14
    Hilary A Seifert,Gil Benedek,Jian Liang,Ha Nguyen,Gail Kent,Arthur A Vandenbark,Julie A Saugstad,Halina Offner

    Stroke is the leading cause of disability in the United States. Sex differences, including smaller infarcts in females and greater involvement of immune-mediated inflammation in males may affect the efficacy of immune-modulating interventions. To address these differences, we sought to identify distinct stroke-modifying mechanisms in female vs. male mice. The current study demonstrated smaller infarcts and increased levels of regulatory CD19+CD5+CD1dhi B10 cells as well as anti-inflammatory CD11b+CD206+ microglia/macrophages in the ipsilateral vs. contralateral hemisphere of female but not male mice undergoing 60min middle cerebral artery occlusion followed by 96h of reperfusion. Moreover, female mice with MCAO had increased total spleen cell numbers but lower B10 levels in spleens. These results elucidate differing sex-dependent regulatory mechanisms that account for diminished stroke severity in females and underscore the need to test immune-modulating therapies for stroke in both males and females.

    更新日期:2019-11-01
  • Characterization of SVEP1, KIAA, and SRPX2 in an in vitro cell culture model of endotoxemia.
    Cell. Immunol. (IF 3.291) Pub Date : 2010-03-20
    Dagmar Schwanzer-Pfeiffer,Eva Rossmanith,Anita Schildberger,Dieter Falkenhagen

    To assess the influence of unknown factors in endotoxemia, a conditioned medium, achieved by the stimulation of THP1 monocytes with lipopolysaccharide (LPS) [4h], was used for the stimulation of human umbilical vein endothelial cells (HUVECs) [16h]. SVEP1, KIAA0247, and SRPX2 were selected after microarray analysis. To study their possible functions, siRNAs of SVEP1, KIAA0247, or SRPX2 were used for the transfection of HUVECs and cells were stimulated with conditioned medium [16h]. Inhibition of SVEP1 expression resulted in an increase of soluble intercellular adhesion molecule (sICAM) 1 (10%) and soluble E-selectin (sE-selectin) (19%). Inhibition of SRPX2 led to an increase of sICAM (11%) and sE-selectin (14%). KIAA0247 negative HUVECs showed a decrease in monocyte chemoattractant protein (MCP) 1 of 16%. SVEP1 and SRPX2 seemed to act as regulators of ICAM1 and E-selectin shedding and influence the expression of membrane bound adhesion molecules.

    更新日期:2019-11-01
  • The differential frequency of Lineage(-)CRTH2(-)CD45(+)NKp44(-)CD117(-)CD127(+)ILC subset in the inflamed terminal ileum of patients with Crohn's disease.
    Cell. Immunol. (IF 3.291) Pub Date : 2016-05-25
    Jian Li,Andria L Doty,Atif Iqbal,Sarah C Glover

    Deregulation of various components of the immune system has been reported in the inflamed gut of Crohn's disease (CD) patients. Innate lymphoid cells (ILCs) are novel innate effector lymphocytes which can rapidly respond to danger signals, from invading pathogens or tissue damage, to maintain homeostasis, especially along the mucosal surfaces. The purpose of this study is to compare composition of the intestinal ILCs subsets of CD patients with differential inflammatory conditions of the terminal ileum, which are marked by distinct histological appearances and mucosal profiles of cytokines. We observed alterations in the frequency of Lineage(-)CRTH2(-)CD45(+)NKp44(-)CD117(-)CD127(+)ILC subset in the inflamed terminal ileum.

    更新日期:2019-11-01
  • A distinct dendritic cell population arises in the thymus of IL-13Rα1-sufficient but not IL-13Rα1-deficient mice.
    Cell. Immunol. (IF 3.291) Pub Date : 2018-06-23
    Subhasis Barik,Mindy Miller,Alexis Cattin-Roy,Tobechukwu Ukah,Habib Zaghouani

    IL-13 receptor alpha 1 (IL-13Rα1) associates with IL-4Rα to form a functional IL-4Rα/IL-13Rα1 heteroreceptor (HR) through which both IL-4 and IL-13 signal. Recently, HR expression was associated with the development of M2 type macrophages which function as antigen presenting cells (APCs). Herein, we show that a subset of thymic resident dendritic cells (DCs) expressing high CD11b (CD11bhi) and intermediate CD11c (CD11cint) arise in HR-sufficient but not HR-deficient mice. These DCs, which originate from the bone marrow are able to take up Ag from the peritoneum, traffic through the spleen and the lymph nodes and carry it to the thymus. In addition, since the DCs are able to present Ag to T cells, express high levels of the costimulatory molecule CD24, and comprise a CD8α+ subset, it is likely that the cells contribute to T cell development and perhaps negative selection of self-reactive lymphocytes.

    更新日期:2019-11-01
  • Rational design of low immunogenic anti CD25 recombinant immunotoxin for T cell malignancies by elimination of T cell epitopes in PE38.
    Cell. Immunol. (IF 3.291) Pub Date : 2017-01-15
    Ronit Mazor,Gilad Kaplan,Dong Park,Youjin Jang,Fred Lee,Robert Kreitman,Ira Pastan

    LMB-2, is a potent recombinant immunotoxin (RIT) that is composed of scFv antibody that targets CD25 (Tac) and a toxin fragment (PE38). It is used to treat T cell leukemias and lymphomas. To make LMB-2 less immunogenic, we introduced a large deletion in domain II and six point mutations in domain III that were previously shown to reduce T cell activation in other RITs. We found that unlike other RITs, deletion of domain II from LMB-2 severely compromised its activity. Rather than deletion, we identified T cell epitopes in domain II and used alanine substitutions to identify point mutations that diminished those epitopes. The novel RIT, LMB-142 contains a 38kDa toxin and nine point mutations that diminished T cell response to the corresponding peptides by an average of 75%. LMB-142 has good cytotoxic activity and has lower nonspecific toxicity in mice. LMB-142 should be more efficient in cancer therapy because more treatment cycles can be given.

    更新日期:2019-11-01
  • Requirement of the expression of 3-phosphoglycerate dehydrogenase for traversing S phase in murine T lymphocytes following immobilized anti-CD3 activation.
    Cell. Immunol. (IF 3.291) Pub Date : 2014-01-18
    Do Youn Jun,Dennis Taub,Francis J Chrest,Young Ho Kim

    Murine resting (G(0)) T lymphocytes contained no detectable mRNA of 3-phosphoglycerate dehydrogenase (PHGDH) catalyzing the first step in the phosphorylated pathway of l-serine biosynthesis. Immobilized anti-CD3 activation of G(0) T cells expressed the PHGDH mRNA in G(1) with a maximum level in S phase. G(0) T cells activated with either immobilized anti-CD3 plus CsA or PBu(2), which failed to drive the activated T cells to enter S phase, did not express the PHGDH mRNA unless exogenous rIL-2 was added. Blocking of IL-2R signaling by adding anti-IL-2 and anti-IL-2Rα resulted in no expression of the PHGDH mRNA during immobilized anti-CD3 activation of G(0) T cells. Deprivation of l-serine from culture medium or addition of antisense PHGDH oligonucleotide significantly reduced [(3)H]TdR incorporation of activated T cells. These results indicate that the PHGDH gene expression, dictated by IL-2R signaling, is a crucial event for DNA synthesis during S phase of activated T cells.

    更新日期:2019-11-01
  • Mountain cedar pollen induces IgE-independent mast cell degranulation, IL-4 production, and intracellular reactive oxygen species generation.
    Cell. Immunol. (IF 3.291) Pub Date : 2011-09-29
    Shuichiro Endo,Daniel J Hochman,Terumi Midoro-Horiuti,Randall M Goldblum,Edward G Brooks

    Cedar pollens cause severe allergic disease throughout the world. We have previously characterized allergenic pollen glycoproteins from mountain cedar (Juniperus ashei) that bind to allergen-specific immunoglobulin E (IgE). In the present report, we investigated an alternative pathway of mast cell activation by mountain cedar pollen extract through IgE-independent mechanisms. We show that mountain cedar pollen directly induces mast cell serotonin and IL-4 release and enhances release induced by IgE cross-linking. Concomitant with mediator release, high levels of intracellular reactive oxygen species (ROS) were generated, and both ROS and serotonin release were inhibited by anti-oxidants. These findings suggest that alternative mechanisms exist whereby pollen exposure enhances allergic inflammatory mediator release through mechanisms that involve ROS. These mechanisms have the potential for enhancing the allergenic potency of pollens.

    更新日期:2019-11-01
  • Inflammation-inducing Th1 and Th17 cells differ in their expression patterns of apoptosis-related molecules.
    Cell. Immunol. (IF 3.291) Pub Date : 2011-09-10
    Cuiyan Tan,Madhu Ramaswamy,Guangpu Shi,Barbara P Vistica,Richard M Siegel,Igal Gery

    Th1 cells are remarkably more susceptible to activation induced cell death than Th17. Here, we compared cultures of these two cell subpopulations for their expression of apoptosis-related molecules when re-exposed to their specific antigen. We also compared the expression of apoptosis-related molecules in the mouse eye with inflammation induced by Th1 or Th17 cells. Using qPCR we found that the mRNA transcript levels of the majority of tested apoptosis-related molecules were higher in the Th1 cultures, and in eyes with Th1-induced inflammation. Apoptotic intrinsic pathway molecules played minor roles in the processes in vitro or in vivo, whereas extrinsic pathway molecules, as well as PD-1, its ligands and Tim3, were heavily involved.

    更新日期:2019-11-01
  • Imaging of lytic granule exocytosis in CD8+ cytotoxic T lymphocytes reveals a modified form of full fusion.
    Cell. Immunol. (IF 3.291) Pub Date : 2011-08-17
    Jose A Martina,Xufeng S Wu,Marta Catalfamo,Takeshi Sakamoto,Chang Yi,John A Hammer

    Here we imaged the exocytosis of lytic granules from human CD8(+) cytotoxic T lymphocytes using rapid total internal reflection microscopy, Lamp-1 tagged with mGFP to follow the fate of the lytic granule membrane, and granzyme A, granzyme B or serglycin tagged with mRFP to follow the fate of lytic granule cargo. Lytic granules were released by full fusion with the plasma membrane, such that the entire granule content for all three cargos visualized was released on a subsecond time scale. The behavior of GFP-Lamp-1 was, however, more complex. While it entered the plasma membrane in all cases, the extent to which it then diffused away from the site of exocytosis varied from nearly complete to highly restricted. Finally, the diffusion properties upon release of the three cargos examined put an upper limit on the size of the macromolecular complex of granzyme and serglycin that is presented to the target cell.

    更新日期:2019-11-01
  • Early expression of stem cell-associated genes within the CD8 compartment after treatment with a tumor vaccine.
    Cell. Immunol. (IF 3.291) Pub Date : 2010-08-10
    M Eric Kohler,William H D Hallett,Qing-Rong Chen,Javed Khan,Bryon D Johnson,Rimas J Orentas

    Using a mouse neuroblastoma cell line, we have demonstrated that vaccination of tumor-free mice with a cell-based vaccine leads to productive immunity and resistance to tumor challenge, while vaccination of tumor-bearing mice does not. The T cell immunity induced by this vaccine, as measured by in vitro assays, is amplified by the depletion of Treg. Our goal is to understand this barrier to the development of protective cellular immunity. mRNA microarray analyses of CD8(+) T cells from naïve or tumor-bearing mice undergoing vaccination were carried out with or without administering anti-CD25 antibody. Gene-expression pathway analysis revealed the presence of CD8(+) T cells expressing stem cell-associated genes early after induction of productive anti-tumor immunity in tumor-free mice, prior to any phenotypic changes, but not in tumor-bearing mice. These data demonstrate that early after the induction of productive immune response, cells within the CD8(+) T cell compartment adopt a stem cell-related genetic phenotype that correlates with increased anti-tumor function.

    更新日期:2019-11-01
  • Depletion of the programmed death-1 receptor completely reverses established clonal anergy in CD4(+) T lymphocytes via an interleukin-2-dependent mechanism.
    Cell. Immunol. (IF 3.291) Pub Date : 2009-02-24
    Kenneth D Bishop,John E Harris,John P Mordes,Dale L Greiner,Aldo A Rossini,Michael P Czech,Nancy E Phillips

    Recent studies have implicated the cell surface receptor Programmed Death-1 (PD-1) in numerous models of T cell anergy, though the specific mechanisms by which the PD-1 signal maintains tolerance is not clear. We demonstrate that the depletion of PD-1 with siRNA results in a complete reversal of clonal anergy in the A.E7 T cell model, suggesting that the mechanism by which PD-1 maintains the anergic phenotype is a T-cell-intrinsic phenomenon, and not one dependent on other cell populations in vivo. We have also shown that the neutralization of IL-2 during restimulation abrogates the effect of PD-1 depletion, suggesting that tolerance mediated by PD-1 is wholly IL-2 dependent, and likewise intrinsic to the tolerized cells.

    更新日期:2019-11-01
  • Multi-faceted control of autoaggression: Foxp3+ regulatory T cells in murine models of organ-specific autoimmune disease.
    Cell. Immunol. (IF 3.291) Pub Date : 2008-03-28
    Richard A O'Connor,Stephen M Anderton

    The discovery of forkhead box p3 (Foxp3) as the critical transcriptional controller of suppressive function in murine CD4(+) T regulatory (Treg) cells has allowed precise analyses of these cells in a range of immunopathological models. Recent data have revealed key roles for Foxp3+ Tregs in murine models of human organ-specific autoimmune conditions. Do these Tregs target the same autoantigens recognized by the autoaggressive T cells that need to be controlled? Under steady state conditions there may not be a need for such a shared recognition to dampen spontaneous anti-self priming in the lymphoid organs. However, when they are needed to control ongoing inflammation, Tregs recognizing autoantigens found in the diseased organ appear to have significantly stronger suppressive powers. We reflect on these observations that clearly have relevance for the translation of Treg-targeting immune therapies to human disease.

    更新日期:2019-11-01
  • Neuroendocrine interactions in the immune system.
    Cell. Immunol. (IF 3.291) Pub Date : 2008-07-16
    Dennis D Taub

    更新日期:2019-11-01
  • Neuroendocrine factors alter host defense by modulating immune function.
    Cell. Immunol. (IF 3.291) Pub Date : 2008-03-11
    Cherie L Butts,Esther M Sternberg

    An increasing body of evidence demonstrates that there is bidirectional communication between the neuroendocrine and immune systems. Interaction between these systems results in a variety of outcomes, including the well documented "sickness behavior" elicited by cytokines of the immune system that can enter the brain and activate second messengers that modify neuronal activity. Crosstalk between the neuroendocrine and immune systems can also result in production of factors by the nervous and endocrine systems that alter immune cell function and subsequent modulation of immune responses against infectious agents and other pathogens. Continued exposure to molecules produced by the neuroendocrine system has also been known to increase susceptibility and/or severity of disease. Furthermore, neuroendocrine factors are thought to play a major role in gender-specific differences in development of certain disorders, including autoimmune/inflammatory diseases that have a two to tenfold higher incidence in females compared to males. Neuroendocrine factors can affect immune cells at the level of gene transcription but have also been shown to modify immune cell activity by interacting with intracellular molecules, resulting in modified ability of these cells to mount a potent immune response. In this review, we will consider various effects of the neuroendocrine system and its proteins on specific populations of immune cells and associated responses in host immunity against pathogens. We will further discuss how this modification of immune cell activity by the neuroendocrine system can contribute to susceptibility/severity of disease development.

    更新日期:2019-11-01
  • Transcriptome analysis of age-, gender- and diet-associated changes in murine thymus.
    Cell. Immunol. (IF 3.291) Pub Date : 2007-05-15
    Ana Lustig,Ashani T Weeraratna,William W Wood,Diane Teichberg,Dorothy Bertak,Arnell Carter,Suresh Poosala,Jeffrey Firman,Kevin G Becker,Alan B Zonderman,Dan L Longo,Dennis D Taub

    The loss of thymic function with age may be due to diminished numbers of T-cell progenitors and the loss of critical mediators within the thymic microenvironment. To assess the molecular changes associated with this loss, we examined transcriptomes of progressively aging mouse thymi, of different sexes and on caloric-restricted (CR) vs. ad libitum (AL) diets. Genes involved in various biological and molecular processes including transcriptional regulators, stress response, inflammation and immune function significantly changed during thymic aging. These differences depended on variables such as sex and diet. Interestingly, many changes associated with thymic aging are either muted or almost completely reversed in mice on caloric-restricted diets. These studies provide valuable insight into the molecular mechanisms associated with thymic aging and emphasize the need to account for biological variables such as sex and diet when elucidating the genomic correlates that influence the molecular pathways responsible for thymic involution.

    更新日期:2019-11-01
  • Editorial.
    Cell. Immunol. (IF 3.291) Pub Date : 2019-08-27
    Jason Lohmueller,Sandra Cascio

    更新日期:2019-11-01
  • Cigarette smoke extract acts directly on CD4 T cells to enhance Th1 polarization and reduce memory potential.
    Cell. Immunol. (IF 3.291) Pub Date : 2018-06-25
    Joanne D Tejero,Nicole C Armand,Caroline M Finn,Kunal Dhume,Tara M Strutt,Karl X Chai,Li-Mei Chen,K Kai McKinstry

    Although cigarette smoke is known to alter immune responses, whether and how CD4 T cells are affected is not well-described. We aimed to characterize how exposure to cigarette smoke extract impacts CD4 T cell effector generation in vitro under Th1-polarizing conditions. Our results demonstrate that cigarette smoke directly acts on CD4 T cells to impair effector expansion by decreasing division and increasing apoptosis. Furthermore, cigarette smoke enhances Th1-associated cytokine production and increases expression of the transcription factor T-bet, the master regulator of Th1 differentiation. Finally, we show that exposure to cigarette smoke extract during priming impairs the ability of effectors to form memory cells. Our findings thus demonstrate that cigarette smoke simultaneously enhances effector functions but promotes terminal differentiation of CD4 T cell effectors. This study may be relevant to understanding how smoking can both aggravate autoimmune symptoms and reduce vaccine efficacy.

    更新日期:2019-11-01
  • The role of exosomes in allograft immunity.
    Cell. Immunol. (IF 3.291) Pub Date : 2018-06-17
    Sandhya Bansal,Monal Sharma,Ranjithkumar R,T Mohanakumar

    Extracellular vesicles are emerging as potent vehicles of intercellular communication. In this review, we focus on a subclass of extracellular vesicles called exosomes. Previously considered an unimportant catch-all, exosomes have recently been recognized for their role in various diseases and their potential for therapeutic use. We have examined the role of exosomes after human lung transplantation and have delineated the composition of circulating exosomes isolated from lung transplant recipients diagnosed with acute and chronic rejection, primary graft dysfunction, and respiratory viral infection. The presence of lung-associated self-antigens (K-alpha 1 Tubulin and collagen V) and mismatched donor HLA in exosomes isolated from lung transplant recipients signifies that these exosomes originated in the transplanted lungs, and therefore dramatically affect transplant biology and immune pathways. Exosomes released from transplanted organs also carry other proteins, costimulatory molecules, and nucleic acids. Therefore, these molecules may be used as biomarkers for allograft rejection and immunity.

    更新日期:2019-11-01
  • Amphotericin B down-regulates Aggregatibacter actinomycetemcomitans-induced production of IL-8 and IL-6 in human gingival epithelial cells.
    Cell. Immunol. (IF 3.291) Pub Date : 2014-07-30
    Haruka Imai,Tsuyoshi Fujita,Mikihito Kajiya,Kazuhisa Ouhara,Tsuyoshi Miyagawa,Shinji Matsuda,Hideki Shiba,Hidemi Kurihara

    Gingival epithelium is the primary barrier against microorganism invasion and produces inflammatory cytokines. Amphotericin B, a major antifungal drug, binds to cholesterol in the mammalian cell membrane in addition to fungal ergosterol. Amphotericin B has been shown to regulate inflammatory cytokines in host cells. To investigate the suppressive effect of amphotericin B on the gingival epithelium, we examined the expression of interleukin (IL)-8 and IL-6 and involvement of MAP kinase in human gingival epithelial cells (HGEC) stimulated by Aggregatibacter actinomycetemcomitans. Amphotericin B and the p38 MAP kinase inhibitor down-regulated the A. actinomycetemcomitans-induced increase in the expression of IL-8 and IL-6 at the mRNA. The ERK inhibitor suppressed the A. actinomycetemcomitans-induced IL-8 mRNA expression. Amphotericin B inhibited the A. actinomycetemcomitans-induced phosphorylation of ERK and p38 MAP kinase. Furthermore, amphotericin B inhibited the A. actinomycetemcomitans-induced production of prostaglandin E2. These results suggest that amphotericin B regulate inflammatory responses in HGEC.

    更新日期:2019-11-01
  • Interleukin-28A promotes IFN-γ production by peripheral blood mononuclear cells from patients with Behçet's disease.
    Cell. Immunol. (IF 3.291) Pub Date : 2014-06-29
    Bing Li,Chufang Xie,Xiaomin Lin,Shao Bo Su

    Behçet's disease (BD) is an autoimmune disease of unknown etiology. Interleukin-28A (IL-28A) promotes immune responses and may participate in the pathogenesis of autoimmune diseases. To examine the role of IL-28A in the pathogenesis of BD, we measured the expression of IFN-γ and IL-17 by IL-28A-stimulated peripheral blood mononuclear cells (PBMCs) from 19 patients with BD and 16 healthy individuals. We found that IFN-γ and IL-17 were undetectable in the sera from BD patients and control subjects. The mRNA expression and protein production of IFN-γ by IL-28A-stimulated PBMCs from BD patients were significantly increased compared to healthy individuals. No significant difference was observed in the mRNA expression and protein production of IL-17 by IL-28A-stimulated PBMCs between BD patients and normal individuals.

    更新日期:2019-11-01
  • Regulation of Salmonella flagellin-induced interleukin-8 in intestinal epithelial cells by muramyl dipeptide.
    Cell. Immunol. (IF 3.291) Pub Date : 2012-11-06
    Fu-Chen Huang

    Toll-like receptor 5 (TLR5) and nucleotide-binding oligomerization domain 2 (Nod2) are two important pattern recognition receptors involved in innate immunity to invading pathogens. Flagellin, recognized by TLR5, is Salmonella's dominant pro-inflammatory determinant in intestinal epithelial cells (IECs). Nod2 has played a pivotal role in protecting against intestinal bacterial infection. Therefore the aim of the study is to investigate regulation of Salmonella flagellin-induced interleukin (IL)-8 (IL-8) in IECs by Nod2 agonist, muramyl dipeptide (MDP). We found that MDP by itself induced only a weak IL-8 secretion in Caco-2 cells. However, it did show synergistic enhancement on flagellin-induced IL-8 production in Caco-2 cells, possibly caused by flagellin-mediated enhanced Nod2 recruitment into cell membrane. By Western blot and siRNA, we showed ERK and NF-κB, Nod2 and Rip2 were involved in the synergistic effect of MDP. These findings suggested that the cooperation of TLR5 and Nod2 in IECs regulates inflammatory response to Salmonella infection.

    更新日期:2019-11-01
  • CXCR7 mediated Giα independent activation of ERK and Akt promotes cell survival and chemotaxis in T cells.
    Cell. Immunol. (IF 3.291) Pub Date : 2011-11-11
    Romsha Kumar,Vishwas Tripathi,Mubashir Ahmad,Neera Nath,Riyaz Ahmad Mir,Shyam S Chauhan,Kalpana Luthra

    Chemokine receptors CXCR7 and CXCR4 bind to the same ligand stromal cell derived factor-1alpha (SDF-1α/CXCL12). We assessed the downstream signaling pathways mediated by CXCL12-CXCR7 interaction in Jurkat T cells. All experiments were carried out after functionally blocking the CXCR4 receptor. CXCL12, on binding CXCR7, induced phosphorylation of extra cellular regulated protein kinases (ERK 1/2) and Akt. Selective inhibition of each signal demonstrated that phosphorylated ERK 1/2 is essential for chemotaxis and survival of T cells whereas activation of Akt promotes only cell survival. Another interesting finding of this study is that CXCL12-CXCR7 interaction under normal physiological conditions does not activate the p38 pathway. Furthermore, we observed that the CXCL12 signaling via CXCR7 is Giα independent. Our findings suggest that CXCR7 promotes cell survival and does not induce cell death in T cells. The CXCL12 signaling via CXCR7 may be crucial in determining the fate of the activated T cells.

    更新日期:2019-11-01
  • Plasma membrane cholesterol plays a critical role in the Salmonella-induced anti-inflammatory response in intestinal epithelial cells.
    Cell. Immunol. (IF 3.291) Pub Date : 2011-09-29
    Fu-Chen Huang

    Our recent study demonstrated that a phosphatidylinositol-3 kinase (PI3K)/Akt-dependent anti-inflammatory pathway was activated by Salmonella in intestinal epithelial cells. Salmonella virulence is dependent on the ability of the bacterium to invade nonphagocytic host cells and then survive and replicate within modified Salmonella-containing vacuoles where cholesterol accumulates. In addition, cholesterol in membrane lipid rafts is frequently a platform for the activation of downstream signaling pathways, including the PI3K/Akt pathway. However, the role of plasma membrane cholesterol in the Salmonella-induced anti-inflammatory response in intestinal epithelial cells has not been elucidated. Here, we show that the effect of plasma membrane cholesterol depletion on the inhibition of Akt activation allows sustained ERK activation and the subsequent upregulation of IL-8 expression. These results demonstrate that plasma membrane cholesterol plays a critical role in the PI3K-dependent anti-inflammatory pathway activated by Salmonella in intestinal epithelial cells.

    更新日期:2019-11-01
  • Monocyte activation by apoptotic cells removal in systemic lupus erythematosus patients.
    Cell. Immunol. (IF 3.291) Pub Date : 2010-09-25
    Lina M Yassin,Mauricio Rojas,Luis A Ramírez,Luis F García,Gloria Vásquez

    Decreased apoptotic cells (ACs) removal has been described as relevant in systemic lupus erythematosus (SLE) pathogenesis. Binding/phagocytosis of ACs was decreased in SLE patients. Blocking experiments suggested a role for CD36 in ACs clearance in healthy controls, not observed in SLE patients. Binding/phagocytosis of ACs induced the production of IL-6, CXCL8 and CCL22 in patients and controls and IL-1β, TNF-α and CCL3 only in healthy controls. ACs clearance induced an increase in CD80 and a decrease in CD86 expression in healthy controls and atherosclerotic patients. However, SLE patients did not up-regulate CD80 expression. The number and expression of CD36 and CD163 in monocytes was not different between the groups. ACs removal induced a down-regulation of CD36 expression in adherent HLA-DR(+) cells in SLE patients but not healthy controls. The decreased binding/phagocytosis of ACs observed in SLE patients, induces a distinct immune response compared with healthy controls.

    更新日期:2019-11-01
  • MicroRNAs are expressed and processed by human primary macrophages.
    Cell. Immunol. (IF 3.291) Pub Date : 2010-04-21
    Aimée J Luers,Olivier D Loudig,Joan W Berman

    Macrophages are crucial to host defense, functioning in innate and cell-mediated immunity. MicroRNAs (miRNAs) are small non-coding RNA molecules that repress transcription and protein production. Little is known about miRNA expression in primary human macrophages, or about how macrophage miRNAs contribute to both normal macrophage function and to the pathogenesis of disease in humans. Using Western blot analyses, we demonstrated the production of miRNA machinery proteins by human primary macrophages. Using two different miRNA array techniques, we identified 119 miRNAs expressed by human primary macrophages, including hsa-let-7a, miR-16, -23a, 30b, -103, -146a, -212, and -378 and validated them by quantitative RT-PCR. Our findings provide a knowledge base to which macrophage miRNA expression in organ-specific macrophages or disease processes may be compared in humans.

    更新日期:2019-11-01
  • A threshold level of TLR9 mRNA predicts cellular responsiveness to CpG-ODN in haematological and non-haematological tumour cell lines.
    Cell. Immunol. (IF 3.291) Pub Date : 2009-07-04
    Areej Assaf,Helia Esteves,S John Curnow,Michael J Browning

    The human toll like receptor 9 (TLR9) detects differences between microbial and host DNA, based on unmethylated deoxycytidyl deoxyguanosine dinucleotide (CpG) motifs, leading to activation of both innate and adaptive immune mechanisms. The synthetic TLR9 agonist, CpG-ODN, can substitute for microbial DNA in these responses, and is in clinical trials as an immunomodulatory agent in diseases as diverse as infections, cancer and allergic disorders. Human TLR9 is expressed on cells of haematopoietic origin (principally plasmacytoid dendritic cells and B cells), but has also been described as being expressed on a number of other cell types. In order to clarify the expression and function of TLR9 in a range of cells of both haematopoietic and non-haematopoietic origin, we investigated the level of expression of TLR9 mRNA, and the ability of the cells to respond to CpG-ODN by upregulation of cell surface markers, cytokine production, cellular proliferation and activation of NFkappaB. Our data show that the cellular response to CpG-ODN depended on a threshold level of expression of TLR9. TLR9 was widely expressed amongst B cell tumours (with the exception of myeloma cell lines), but we did not find either threshold levels of expression of TLR9 or responses to CpG-ODN in several myeloma or myeloid tumour cell lines or any non-haematological tumour cell lines tested in our study. TLR9-positive cells varied significantly in their responses to CpG-ODN, and the level of TLR9 expression beyond the threshold did not correlate with the magnitude of the response to CpG-ODN. Finally, CpG-ODN induced NFkappaB activation and increased cellular proliferation in Hek293 cells that had been stably transfected with hTLR9, but did not affect the expression of surface markers or synthesis of IL-6, IL-10 or TNF-alpha. Thus both haematological and non-haematological cells expressing appropriate levels of TLR9 respond to CpG-ODN, but the nature of the TLR9-mediated response is dependent on cell type.

    更新日期:2019-11-01
  • Deletion of the C6orf120 gene with unknown function ameliorates autoimmune hepatitis induced by concanavalin A.
    Cell. Immunol. (IF 3.291) Pub Date : 2018-05-12
    Man-Ka Zhang,Hui-Min Ma,Jian Zhang,Xin-Cheng Song,Xiao-Hui Ye,Yu-Feng Li,Yi-Fan Zhang,Ling-Ling He,Hong-Shan Wei,Xin Li

    The present study was conducted to characterize the C6orf120 gene, by using C6orf120 gene-deleted rats (C6orf120-/-), to determine its role in the development and severity of autoimmune hepatitis induced by concanavalin A (Con A), as well as the underlying mechanisms. We found that following Con A injection, C6orf120-/- rats were less susceptible to developing autoimmune hepatitis with low levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) post challenge. Additionally, C6orf120 deficiency increased the frequency of cluster of differentiation (CD)4+ CD25+ Forkhead box P3+ regulatory T cells (Tregs) among intrahepatic lymphocytes, splenocytes, peripheral blood mononuclear cells, and CD4+ T in vitro. Moreover, C6orf120 deficiency downregulated interleukin (IL)-1β, IL-6, tumor necrosis factor alpha-α, interferon-γ and IL-17a secretion in the plasma and liver tissues. Our results indicated that the C6orf120 gene-deleted rats were less susceptible to Con A-induced autoimmune hepatitis, which may be partly related to the increased frequency of Tregs and inhibited secretion of inflammatory cytokines.

    更新日期:2019-11-01
  • Balancing immunity and tolerance in gene therapy for inherited and acquired diseases.
    Cell. Immunol. (IF 3.291) Pub Date : 2019-06-24
    David W Scott,Federico Mingozzi

    更新日期:2019-11-01
  • Special Issue: The role of glycans in immunity and disease.
    Cell. Immunol. (IF 3.291) Pub Date : 2018-12-18
    Brian A Cobb,Mark B Jones

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • 更新日期:2019-11-01
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