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1.
The atypical IκB protein IκBNS is important for Toll‐like receptor‐induced interleukin‐10 production in B cells 下载免费PDF全文
Minami Miura Naoki Hasegawa Mitsuo Noguchi Kenkichi Sugimoto Maki Touma 《Immunology》2016,147(4):453-463
Although a major function of B cells is to mediate humoral immunity by producing antigen‐specific antibodies, a specific subset of B cells is important for immune suppression, which is mainly mediated by the secretion of the anti‐inflammatory cytokine interleukin‐10 (IL‐10). However, the mechanism by which IL‐10 is induced in B cells has not been fully elucidated. Here, we report that IκBNS, an inducible nuclear IκB protein, is important for Toll‐like receptor (TLR)‐mediated IL‐10 production in B cells. Studies using IκBNS knockout mice revealed that the number of IL‐10‐producing B cells is reduced in IκBNS?/? spleens and that the TLR‐mediated induction of cytoplasmic IL‐10‐positive cells and IL‐10 secretion in B cells are impaired in the absence of IκBNS. The impairment of IL‐10 production by a lack of IκBNS was not observed in TLR‐triggered macrophages or T‐cell‐receptor‐stimulated CD4+ CD25+ T cells. In addition, IκBNS‐deficient B cells showed reduced expression of Prdm1 and Irf4 and failed to generate IL‐10+ CD138+ plasmablasts. These results suggest that IκBNS is selectively required for IL‐10 production in B cells responding to TLR signals, so defining an additional role for IκBNS in the control of the B‐cell‐mediated immune responses. 相似文献
2.
OX40 controls effector CD4+ T‐cell expansion,not follicular T helper cell generation in acute Listeria infection 下载免费PDF全文
Clare L. Marriott Emma C. Mackley Cristina Ferreira Marc Veldhoen Hideo Yagita David R. Withers 《European journal of immunology》2014,44(8):2437-2447
To investigate the importance of OX40 signals for physiological CD4+ T‐cell responses, an endogenous antigen‐specific population of CD4+ T cells that recognise the 2W1S peptide was assessed and temporal control of OX40 signals was achieved using blocking or agonistic antibodies (Abs) in vivo. Following infection with Listeria monocytogenes expressing 2W1S peptide, OX40 was briefly expressed by the responding 2W1S‐specific CD4+ T cells, but only on a subset that co‐expressed effector cell markers. This population was specifically expanded by Ab‐ligation of OX40 during priming, which also caused skewing of the memory response towards effector memory cells. Strikingly, this greatly enhanced effector response was accompanied by the loss of T follicular helper (TFH) cells and germinal centres. Mice deficient in OX40 and CD30 showed normal generation of TFH cells but impaired numbers of 2W1S‐specific effector cells. OX40 was not expressed by 2W1S‐specific memory cells, although it was rapidly up‐regulated upon challenge whereupon Ab‐ligation of OX40 specifically affected the effector subset. In summary, these data indicate that for CD4+ T cells, OX40 signals are important for generation of effector T cells rather than TFH cells in this response to acute bacterial infection. 相似文献
3.
T‐cell receptor activation of human CD4+ T cells shifts the innate TLR response from CXCL8hiIFN‐γnull to CXCL8loIFN‐γhi 下载免费PDF全文
Toll‐like receptors (TLRs) play a major part in providing innate immunity against pathogenic microorganisms. Recent studies show that these receptors are also expressed on T cells, which are the sentinels of adaptive immunity. Here, we have investigated the regulatory role of the T‐cell receptor in the functioning of these innate receptors in T cells. We show that freshly isolated human CD4+ T cells readily secrete the neutrophil chemoattractant CXCL8 upon activation with the TLR ligands Pam3CSK and flagellin. In contrast, TCR‐activated cells secrete considerably less CXCL8 but start producing IFN‐γ upon stimulation with TLR agonists in the absence of concomitant TCR engagement. These T cells show increased activation of p38 and JNK MAP‐kinases in response to TLR stimulation, and inhibition of p38 abrogates TLR‐induced IFN‐γ secretion. The shifting of the T‐cell innate immune response from CXCL8hiIFN‐γnull in freshly isolated to CXCL8loIFN‐γhi in activated T cells is also observed in response to endogenous innate stimulus, IL‐1. These results suggest that the innate immune response of human CD4+ T cells switches from a proinflammatory to an effector type following activation of these cells through the antigen receptor. 相似文献
4.
Masashi Emoto Yoshiko Emoto Stefan H. E. Kaufmann 《European journal of immunology》1995,25(12):3321-3325
Experimental infection of mice with the intracellular bacterium, Listeria monocytogenes, provides a paragon model for immune defence dominated by T helper type 1 (Th1) responses. Potent production of interleukin (IL)-12 by infected macrophages is considered the determining factor in Th1 cell development. In contrast, it is assumed that IL-4 producers remain virtually unstimulated in listeriosis. In the liver, the major target organ of listeriosis, an unusual T lymphocyte population exists with the intriguing phenotype CD4+NK1.1+ TCRα/βintermediate (TCRα/βint). Here we show that IL-4-producing CD4+NK1.1+TCRα/βint liver lymphocytes are down-regulated early in listeriosis. We assume that curtailment of IL-4-producing CD4+NK1.1+TCRα/βint liver lymphocytes promotes unconstrained development of Th1 cells which are central to protection against intracellular bacteria. 相似文献
5.
Nuno Viegas Lisa Andzinski Ching‐Fang Wu Ronja‐Melinda Komoll Nelson Gekara Kurt E. Dittmar Siegfried Weiss Jadwiga Jablonska 《European journal of immunology》2013,43(10):2626-2637
Natural killer (NK) cells are key components of the immune system involved in several immune reactions, including the clearance of intracellular pathogens. When activated, NK cells rapidly secrete particular cytokines that activate innate immunity and facilitate development of adaptive responses. Conflicting reports on the role of NK cells during infection by Listeria monocytogenes can be found in the literature. Here, we demonstrate that during lethal infection by L. monocytogenes, activation of NK cells via the costimulatory molecule CD27 leads to excessive IFN‐γ production. This impairs innate anti‐bacterial host defenses by inducing downregulation of CXCR2 on granulocytes and consequently inhibiting their recruitment to the sites of infection. The use of antibodies to block CD27 signaling or to deplete IFN‐γ was sufficient to rescue mice from lethal challenge by L. monocytogenes. Our findings contribute to a better understanding of the importance of CD27 signaling in activation of NK cells and should provide new ways of interfering with infections. 相似文献
6.
CXCR3high CD8+ T cells with naïve phenotype and high capacity for IFN‐γ production are generated during homeostatic T‐cell proliferation 下载免费PDF全文
Aiko Kato Akifumi Takaori‐Kondo Nagahiro Minato Yoko Hamazaki 《European journal of immunology》2018,48(10):1663-1678
Naïve phenotype (NP) T cells spontaneously initiate homeostatic proliferation (HP) as T‐cell output is reduced because of physiologic thymic involution with age. However, the effects of sustained HP on overall immune function are poorly understood. We demonstrated that the NP CD8+ T cell population in adult thymectomized mice showing accelerated HP has an increased capacity for TCR‐mediated interferon‐γ and tumor necrosis factor α production, which is attributed to an increase in CXCR3+ cells in the NP CD8+ T cell population. The CXCR3+ NP CD8+ T cells developed during persistent HP with a slow cell division rate, but rarely during robust antigen‐driven proliferation with a fast cell division rate. In ontogeny, the proportions of CXCR3+ cells in the NP CD8+ T cell population showed a biphasic profile, which was high at the newborn and aged stages. Upon transfer, CXCR3+ NP CD8+ T cells, but not CXCR3? NP CD8+ T cells, potently enhanced Th17‐mediated inflammatory tissue reactions in vivo. Furthermore, CXCR3high NP CD8+ T cells with similar features were also detected at variable levels in healthy human blood. These results suggest that CXCR3+ NP CD8+ T cells generated during physiological HP significantly impact overall immunity at the immunologically vulnerable neonatal and aged stages. 相似文献
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Elisa Lupino Barbara Buccinn�� Cristina Ramondetti Annarosa Lomartire Giovanni De Marco Emanuela Ricotti Pier-Angelo Tovo Maria T Rinaudo Marco Piccinini 《Immunology》2010,131(2):231-241
Stimulation of naïve CD4+ T cells through engagement of the T‐cell receptor (TCR) and the CD28 co‐receptor initiates cell proliferation which critically depends on interleukin (IL)‐2 secretion and subsequent autocrine signalling via the IL‐2 receptor. However, several studies indicate that in CD28‐costimulated T cells additional IL‐2‐independent signals are also required for cell proliferation. In this study, using a neutralizing anti‐human IL‐2 antibody and two selective, structurally unrelated, cell‐permeable I‐κB kinase (IKK) inhibitors, BMS‐345541 and PS‐1145, we show that in human naïve CD4+ T cells stimulated through a short engagement of the TCR and the CD28 co‐receptor, IKK controls the expression of the cell cycle regulatory proteins cyclin D3, cyclin E and cyclin‐dependent kinase 2 (CDK2) and the stability of the F‐box protein S‐phase kinase‐associated protein 2 (SKP2) and its co‐factor CDC28 protein kinase regulatory subunit 1B (CKS1B), through IL‐2‐independent mechanisms. 相似文献
9.
Florencia Sabbione María L. Gabelloni Glenda Ernst María S. Gori Gabriela Salamone Matías Oleastro Analía Trevani Jorge Geffner Carolina C. Jancic 《European journal of immunology》2014,44(3):819-830
γδ T cells have been shown to stimulate the recruitment and activation of neutrophils through the release of a range of cytokines and chemokines. Here, we investigated the reverse relationship, showing that human neutrophils suppress the function of human blood γδ T cells. We show that the upregulation of CD25 and CD69 expression, the production of IFN‐γ, and the proliferation of γδ T cells induced by (E)‐1‐hydroxy‐2‐methylbut‐2‐enyl 4‐diphosphate are inhibited by neutrophils. Spontaneous activation of γδ T cells in culture is also suppressed by neutrophils. We show that inhibitors of prostaglandin E2 and arginase I do not exert any effect, although, in contrast, catalase prevents the suppression of γδ T cells induced by neutrophils, suggesting the participation of neutrophil‐derived ROS. We also show that the ROS‐generating system xanthine/xanthine oxidase suppresses γδ T cells in a similar fashion to neutrophils, while neutrophils from chronic granulomatous disease patients only weakly inhibit γδ T cells. Our results reveal a bi‐directional cross‐talk between γδ T cells and neutrophils: while γδ T cells promote the recruitment and the activation of neutrophils to fight invading pathogens, neutrophils in turn suppress the activation of γδ T cells to contribute to the resolution of inflammation. 相似文献
10.
CD70 and IFN‐1 selectively induce eomesodermin or T‐bet and synergize to promote CD8+ T‐cell responses 下载免费PDF全文
Han Dong Nathan A. Franklin Shane B. Ritchea Hideo Yagita Martin J. Glennie Timothy N. J. Bullock 《European journal of immunology》2015,45(12):3289-3301
CD70‐mediated stimulation of CD27 is an important cofactor of CD4+ T‐cell licensed dendritic cells (DCs). However, it is unclear how CD70‐mediated stimulation of T cells is integrated with signals that emanate from signal 3 pathways, such as type‐1 interferon (IFN‐1) and IL‐12. We find that while stimulation of CD27 in isolation drives weak EomesoderminhiT‐betlo CD8+ T‐cell responses to OVA immunization, profound synergistic expansion is achieved by cotargeting TLR. This cooperativity can substantially boost antiviral CD8+ T‐cell responses during acute infection. Concomitant stimulation of TLR significantly increases per cell IFN‐γ production and the proportion of the population with characteristics of short‐lived effector cells, yet also promotes the ability to form long‐lived memory. Notably, while IFN‐1 contributes to the expression of CD70 on DCs, the synergy between CD27 and TLR stimulation is dependent upon IFN‐1's effect directly on CD8+ T cells, and is associated with the increased expression of T‐bet in T cells. Surprisingly, we find that IL‐12 fails to synergize with CD27 stimulation to promote CD8+ T‐cell expansion, despite its capacity to drive effector CD8+ T‐cell differentiation. Together, these data identify complex interactions between signal 3 and costimulatory pathways, and identify opportunities to influence the differentiation of CD8+ T‐cell responses. 相似文献
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Central tolerance spares the private high‐avidity CD4+ T‐cell repertoire specific for an islet antigen in NOD mice 下载免费PDF全文
Although central tolerance induces the deletion of most autoreactive T cells, some autoreactive T cells escape thymic censorship. Whether potentially harmful autoreactive T cells present distinct TCRαβ features remains unclear. Here, we analyzed the TCRαβ repertoire of CD4+ T cells specific for the S100β protein, an islet antigen associated with type 1 diabetes. We found that diabetes‐resistant NOD mice deficient for thymus specific serine protease (TSSP), a protease that impairs class II antigen presentation by thymic stromal cells, were hyporesponsive to the immunodominant S100β1‐15 epitope, as compared to wild‐type NOD mice, due to intrathymic negative selection. In both TSSP‐deficient and wild‐type NOD mice, the TCRαβ repertoire of S100β‐specific CD4+ T cells though diverse showed a specific bias for dominant TCRα rearrangements with limited CDR3α diversity. These dominant TCRα chains were public since they were found in all mice. They were of intermediate‐ to low‐avidity. In contrast, high‐avidity T cells expressed unique TCRs specific to each individual (private TCRs) and were only found in wild‐type NOD mice. Hence, in NOD mice, the autoreactive CD4+ T‐cell compartment has two major components, a dominant and public low‐avidity TCRα repertoire and a private high‐avidity CD4+ T‐cell repertoire; the latter is deleted by re‐enforced negative selection. 相似文献
13.
CD8+ T cells of Listeria monocytogenes‐infected mice recognize both linear and spliced proteasome products 下载免费PDF全文
Anouk C. M. Platteel Michele Mishto Kathrin Textoris‐Taube Christin Keller Juliane Liepe Dirk H. Busch Peter M. Kloetzel Alice J. A. M. Sijts 《European journal of immunology》2016,46(5):1109-1118
CD8+ T cells responding to infection recognize pathogen‐derived epitopes presented by MHC class‐I molecules. While most of such epitopes are generated by proteasome‐mediated antigen cleavage, analysis of tumor antigen processing has revealed that epitopes may also derive from proteasome‐catalyzed peptide splicing (PCPS). To determine whether PCPS contributes to epitope processing during infection, we analyzed the fragments produced by purified proteasomes from a Listeria monocytogenes polypeptide. Mass spectrometry identified a known H‐2Kb‐presented linear epitope (LLO296‐304) in the digests, as well as four spliced peptides that were trimmed by ERAP into peptides with in silico predicted H‐2Kb binding affinity. These spliced peptides, which displayed sequence similarity with LLO296‐304, bound to H‐2Kb molecules in cellular assays and one of the peptides was recognized by CD8+ T cells of infected mice. This spliced epitope differed by one amino acid from LLO296‐304 and double staining with LLO296‐304‐ and spliced peptide‐folded MHC multimers showed that LLO296‐304 and its spliced variant were recognized by the same CD8+ T cells. Thus, PCPS multiplies the variety of peptides that is processed from an antigen and leads to the production of epitope variants that can be recognized by cross‐reacting pathogen‐specific CD8+ T cells. Such mechanism may reduce the chances for pathogen immune evasion. 相似文献
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Mesenteric lymph nodes contribute to proinflammatory Th17‐cell generation during inflammation of the small intestine in mice 下载免费PDF全文
Takeshi Kawabe Nobu Suzuki Satoshi Yamaki Shu‐lan Sun Atsuko Asao Yuko Okuyama Takanori So Yoichiro Iwakura Naoto Ishii 《European journal of immunology》2016,46(5):1119-1131
T cells of the small intestine, including Th17 cells, are critically involved in host protection from microbial infection, and also contribute to the pathogenesis of small bowel inflammatory disorders. Accumulating evidence suggests that mesenteric lymph nodes (MLNs) play important roles in gut‐tropic T‐cell generation, although it is still unclear if MLNs are involved in the pathogenesis of small intestine inflammation. To address this issue, we analyzed the roles of both MLNs and Peyer's patches (PPs) by evaluating MLN‐ or PP‐deficient mice in an experimental model of small intestine inflammation, induced by CD3‐specific mAb injection. Interestingly, MLNs, but not PPs, were essential for the pathogenesis of intestinal inflammation, in particular the accumulation and infiltration of CD4+ T‐cell populations, including Th17 cells, from the blood. In addition, CD4+ T‐cell accumulation was dependent on the function of the α4β7 integrin. Furthermore, MLN removal led to a significantly reduced number of peripheral α4β7+ CD4+ effector memory T cells under normal conditions, suggesting that MLNs may play a role in maintaining the number of gut‐tropic CD4+ effector memory T cells circulating in the blood. Taken together, the present study highlights the important role of MLNs in contributing to the pathogenesis of small intestine inflammation. 相似文献
17.
Epitope‐specific CD4+, but not CD8+, T‐cell responses induced by recombinant influenza A viruses protect against Mycobacterium tuberculosis infection 下载免费PDF全文
Manuela Flórido Roman Pillay Caitlin M. Gillis Yingju Xia Stephen J. Turner James A. Triccas John Stambas Warwick J. Britton 《European journal of immunology》2015,45(3):780-793
Tuberculosis remains a global health problem, in part due to failure of the currently available vaccine, BCG, to protect adults against pulmonary forms of the disease. We explored the impact of pulmonary delivery of recombinant influenza A viruses (rIAVs) on the induction of Mycobacterium tuberculosis (M. tuberculosis)‐specific CD4+ and CD8+ T‐cell responses and the resultant protection against M. tuberculosis infection in C57BL/6 mice. Intranasal infection with rIAVs expressing a CD4+ T‐cell epitope from the Ag85B protein (PR8.p25) or CD8+ T‐cell epitope from the TB10.4 protein (PR8.TB10.4) generated strong T‐cell responses to the M. tuberculosis‐specific epitopes in the lung that persisted long after the rIAVs were cleared. Infection with PR8.p25 conferred protection against subsequent M. tuberculosis challenge in the lung, and this was associated with increased levels of poly‐functional CD4+ T cells at the time of challenge. By contrast, infection with PR8.TB10.4 did not induce protection despite the presence of IFN‐γ‐producing M. tuberculosis‐specific CD8+ T cells in the lung at the time of challenge and during infection. Therefore, the induction of pulmonary M. tuberculosis epitope‐specific CD4+, but not CD8+ T cells, is essential for protection against acute M. tuberculosis infection in the lung. 相似文献
18.
OX40 and IL‐7 play synergistic roles in the homeostatic proliferation of effector memory CD4+ T cells 下载免费PDF全文
Takeshi Kawabe Yuko Okuyama Nobu Suzuki Pejman Soroosh Seyed Fazlollah Mousavi Hiroyuki Nagashima Shu‐lan Sun Takanori So Takeshi Sasaki Hideo Harigae Kazuo Sugamura Hironori Kudo Motoshi Wada Masaki Nio Naoto Ishii 《European journal of immunology》2014,44(10):3015-3025
T‐cell homeostasis preserves the numbers, the diversity and functional competence of different T‐cell subsets that are required for adaptive immunity. Naïve CD4+ T (TN) cells are maintained in the periphery via the common γ‐chain family cytokine IL‐7 and weak antigenic signals. However, it is not clear how memory CD4+ T‐cell subsets are maintained in the periphery and which factors are responsible for the maintenance. To examine the homeostatic mechanisms, CFSE‐labeled CD4+CD44highCD62Llow effector memory T (TEM) cells were transferred into sublethally‐irradiated syngeneic C57BL/6 mice, and the systemic cell proliferative responses, which can be divided distinctively into fast and slow proliferations, were assessed by CFSE dye dilution. We found that the fast homeostatic proliferation of TEM cells was strictly regulated by both antigen and OX40 costimulatory signals and that the slow proliferation was dependent on IL‐7. The simultaneous blockade of both OX40 and IL‐7 signaling completely inhibited the both fast and slow proliferation. The antigen‐ and OX40‐dependent fast proliferation preferentially expanded IL‐17‐producing helper T cells (Th17 cells). Thus, OX40 and IL‐7 play synergistic, but distinct roles in the homeostatic proliferation of CD4+ TEM cells. 相似文献
19.
Balanced Bcl‐3 expression in murine CD4+ T cells is required for generation of encephalitogenic Th17 cells 下载免费PDF全文
Ilgiz A. Mufazalov Janina Kuschmann David Andruszewski Joumana Masri Laureen A. Gabriel Petra Adams Sonja Reissig Nadine Hövelmeyer Ari Waisman 《European journal of immunology》2017,47(8):1335-1341
20.
T‐bet regulates differentiation of forkhead box protein 3+ regulatory T cells in programmed cell death‐1‐deficient mice 下载免费PDF全文
M. Tahara Y. Kondo M. Yokosawa H. Tsuboi S. Takahashi S. Shibayama I. Matsumoto T. Sumida 《Clinical and experimental immunology》2015,179(2):197-209
Programmed cell death‐1 (PD‐1) plays an important role in peripheral T cell tolerance, but whether or not it affects the differentiation of helper T cell subsets remains elusive. Here we describe the importance of PD‐1 in the control of T helper type 1 (Th1) cell activation and development of forkhead box protein 3 (FoxP3+) regulatory T cells (Tregs). PD‐1‐deficient T cell‐specific T‐bet transgenic (P/T) mice showed growth retardation, and the majority died within 10 weeks. P/T mice showed T‐bet over‐expression, increased interferon (IFN)‐γ production by CD4+ T cells and significantly low FoxP3+ Treg cell percentage. P/T mice developed systemic inflammation, which was probably induced by augmented Th1 response and low FoxP3+ Treg count. The study identified a unique, previously undescribed role for PD‐1 in Th1 and Treg differentiation, with potential implication in the development of Th1 cell‐targeted therapy. 相似文献