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1.
T cell receptor alpha variable 12‐2 bias in the immunodominant response to Yellow fever virus
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Amandine Bovay Vincent Zoete Garry Dolton Anna M. Bulek David K. Cole Pierre J. Rizkallah Anna Fuller Konrad Beck Olivier Michielin Daniel E. Speiser Andrew K. Sewell Silvia A. Fuertes Marraco 《European journal of immunology》2018,48(2):258-272
The repertoire of human αβ T‐cell receptors (TCRs) is generated via somatic recombination of germline gene segments. Despite this enormous variation, certain epitopes can be immunodominant, associated with high frequencies of antigen‐specific T cells and/or exhibit bias toward a TCR gene segment. Here, we studied the TCR repertoire of the HLA‐A*0201‐restricted epitope LLWNGPMAV (hereafter, A2/LLW) from Yellow Fever virus, which generates an immunodominant CD8+ T cell response to the highly effective YF‐17D vaccine. We discover that these A2/LLW‐specific CD8+ T cells are highly biased for the TCR α chain TRAV12‐2. This bias is already present in A2/LLW‐specific naïve T cells before vaccination with YF‐17D. Using CD8+ T cell clones, we show that TRAV12‐2 does not confer a functional advantage on a per cell basis. Molecular modeling indicated that the germline‐encoded complementarity determining region (CDR) 1α loop of TRAV12‐2 critically contributes to A2/LLW binding, in contrast to the conventional dominant dependence on somatically rearranged CDR3 loops. This germline component of antigen recognition may explain the unusually high precursor frequency, prevalence and immunodominance of T‐cell responses specific for the A2/LLW epitope. 相似文献
2.
Clonotype‐specific avidity influences the dynamics and hierarchy of virus‐specific regulatory and effector CD4+ T‐cell responses
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Jie Liu Shirley Cao Gretchen Peppers Sung‐Han Kim Barney S. Graham 《European journal of immunology》2014,44(4):1058-1068
A key component of immunity against viruses, CD4+ T cells expand and differentiate into functional subsets upon primary infection, where effector (Teff) cells facilitate infection control and regulatory (Treg) cells mitigate immunopathology. After secondary infection, Teff cells mount a robust response from the memory pool. Here, we show that Treg‐cell responses are diminished upon secondary infection, and Treg‐cell response dynamics are associated more with T‐cell receptors (TCRs) repertoire and avidity than with epitope specificity. In the murine model, the IAbM209 epitope of respiratory syncytial virus is recognized by both CD4+ Treg and Teff cells, while the IAbM226 epitope is recognized almost exclusively by CD4+ Teff cells expressing high avidity TCR Vβ8.1/8.2 and dominating the CD4+ T‐cell response during primary and secondary infections. IAbM209‐Teff cells express relatively low avidity TCRs during early primary infection, but high avidity TCR Vβ7‐expressing IAbM209‐Teff cells emerge during the late phase, and become dominant after secondary infection. The emerging high avidity IAbM209‐Teff cells outcompete IAbM209‐Treg cells that share the same epitope, but have low avidity and are restricted to TCR Vβ2 and Vβ6 subpopulations. These data indicate that MHC‐peptide‐TCR interactions can produce different kinetic and functional profiles in CD4+ T‐cell populations even when responding to the same epitope. 相似文献
3.
Julien Gommeaux Claude Grégoire Prudence Nguessan Mireille Richelme Marie Malissen Sylvie Guerder Bernard Malissen Alice Carrier 《European journal of immunology》2009,39(4):956-964
Thymus‐specific serine protease (TSSP) was initially reported as a putative protease specifically expressed in the endosomal compartment of cortical thymic epithelial cells (cTEC). As such, TSSP is potentially involved in the presentation of the self‐peptides that are bound to MHC class II molecules expressed at the cTEC surface and are involved in the positive selection of CD4+ thymocytes. We tested this hypothesis by generating mutant mice deprived of Prss16, the gene encoding TSSP. TSSP‐deficient mice produced normal numbers of T cells, despite a decrease in the percentage of cTEC expressing high surface levels of MHC class II. By using sensitive transgenic models expressing MHC class II‐restricted TCR transgenes (Marilyn and OT‐II), we showed that the absence of TSSP markedly impaired the selection of Marilyn and OT‐II CD4+ T cells. In contrast, selection of CD8+ T cells expressing an MHC class I‐restricted TCR transgene (OT‐I) was unaffected. Therefore, TSSP is involved in the positive selection of some CD4+ T lymphocytes and likely constitutes the first serine protease to play a function in the intrathymic presentation of self‐peptides bound to MHC class II complexes. 相似文献
4.
The adaptor protein SAP regulates type II NKT‐cell development,cytokine production,and cytotoxicity against lymphoma
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Sreya Bagchi Susanna L. Cardell Paul L. Stein Chyung‐Ru Wang 《European journal of immunology》2014,44(12):3646-3657
CD1d‐restricted NKT cells represent a unique lineage of immunoregulatory T cells that are divided into two groups, type I and type II, based on their TCR usage. Because there are no specific tools to identify type II NKT cells, little is known about their developmental requirements and functional regulation. In our previous study, we showed that signaling lymphocytic activation molecule associated protein (SAP) is essential for the development of type II NKT cells. Here, using a type II NKT‐cell TCR transgenic mouse model, we demonstrated that CD1d‐expressing hematopoietic cells, but not thymic epithelial cells, meditate efficient selection of type II NKT cells. Furthermore, we showed that SAP regulates type II NKT‐cell development by controlling early growth response 2 protein and promyelocytic leukemia zinc finger expression. SAP‐deficient 24αβ transgenic T cells (24αβ T cells) exhibited an immature phenotype with reduced Th2 cytokine‐producing capacity and diminished cytotoxicity to CD1d‐expressing lymphoma cells. The impaired IL‐4 production by SAP‐deficient 24αβ T cells was associated with reduced IFN regulatory factor 4 and GATA‐3 induction following TCR stimulation. Collectively, these data suggest that SAP is critical for regulating type II NKT cell responses. Aberrant responses of these T cells may contribute to the immune dysregulation observed in X‐linked lymphoproliferative disease caused by mutations in SAP. 相似文献
5.
Katherine Kedzierska Sophie A. Valkenburg Carole Guillonneau Francois‐Xavier Hubert Tania Cukalac Joan M. Curtis John Stambas Hamish S. Scott Lukasz Kedzierski Vanessa Venturi Miles P. Davenport 《European journal of immunology》2010,40(3):849-858
TCR repertoire diversity is important for the protective efficacy of CD8+ T cells, limiting viral escape and cross‐reactivity between unrelated epitopes. The exact mechanism for selection of restricted versus diverse TCR repertoires is far from clear, although one thought is that the epitopes resembling self‐peptides might select a limited array of TCR due to the deletion of autoreactive TCR. The molecule Aire promotes the expression of tissue‐specific Ag on thymic medullary epithelial cells and the deletion of autoreactive cells, and in the absence of Aire autoreactive cells persist. However, the contribution of Aire‐dependent peptides to the selection of the Ag‐specific TCR repertoire remains unknown. In this study, we dissect restricted (DbNP366%+CD8+) and diverse (DbPA224%+CD8+, KdNP147%+CD8+) TCR repertoires responding to three influenza‐derived peptides in Aire‐deficient mice on both B6 and BALB/c backgrounds. Our study shows that the number, qualitative characteristics and TCR repertoires of all influenza‐specific, DbNP366%+CD8+, DbPA224%+CD8+ and KdNP147%+CD8+ T cells are not significantly altered in the absence of Aire. This provides the first demonstration that the selection of an Ag‐specific T‐cell repertoire is not significantly perturbed in the absence of Aire. 相似文献
6.
Maike Hofmann Anna Oschowitzer Stefan R. Kurzhals Caroline C. Krüger Hanspeter Pircher 《European journal of immunology》2013,43(9):2295-2304
The thymus is a primary lymphoid organ responsible for production and selection of T cells. Nonetheless, mature T cells and in particular activated T cells can reenter the thymus. Here, we identified memory CD8+ T cells specific for lymphocytic choriomeningitis virus or vaccinia virus in the thymus of mice long‐time after the infection. CD8+ T cells were mainly located in the thymic medulla, but also in the cortical areas. Interestingly, virus‐specific memory CD8+ T cells in the thymus expressed the cell surface markers CD69 and CD103 that are characteristic of tissue‐resident memory T cells in a time‐dependent manner. Kinetic analyses and selective depletion of peripheral CD8+ T cells by antibodies further revealed that thymic virus‐specific memory CD8+ T cells did not belong to the circulating pool of lymphocytes. Finally, we demonstrate that these thymus‐resident virus‐specific memory CD8+ T cells efficiently mounted a secondary proliferative response, exhibited immediate effector functions and were able to protect the thymus from lymphocytic choriomeningitis virus reinfection. In conclusion, the present study not only describes for the first time virus‐specific memory CD8+ T cells with characteristics of tissue‐resident memory T (TRM) cells in a primary lymphoid organ but also extends our knowledge about local T‐cell immunity in the thymus. 相似文献
7.
The type 1 diabetes resistance locus B10 Idd9.3 mediates impaired B‐cell lymphopoiesis and implicates microRNA‐34a in diabetes protection
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Gregory J. Berry Lynn R. Budgeon Timothy K. Cooper Neil D. Christensen Hanspeter Waldner 《European journal of immunology》2014,44(6):1716-1727
NOD.B10 Idd9.3 mice are congenic for the insulin‐dependent diabetes (Idd) Idd9.3 locus, which confers significant type 1 diabetes (T1D) protection and encodes 19 genes, including microRNA (miR)‐34a, from T1D‐resistant C57BL/10 mice. B cells have been shown to play a critical role in the priming of autoantigen‐specific CD4+ T cells in T1D pathogenesis in non‐obese diabetic (NOD) mice. We show that early B‐cell development is impaired in NOD.B10 Idd9.3 mice, resulting in the profound reduction of transitional and mature splenic B cells as compared with NOD mice. Molecular analysis revealed that miR‐34a expression was significantly higher in B‐cell progenitors and marginal zone B cells from NOD.B10 Idd9.3 mice than in NOD mice. Furthermore, miR‐34a expression in these cell populations inversely correlated with levels of Foxp1, an essential regulator of B‐cell lymphopoiesis, which is directly repressed by miR‐34a. In addition, we show that islet‐specific CD4+ T cells proliferated inefficiently when primed by NOD.B10 Idd9.3 B cells in vitro or in response to endogenous autoantigen in NOD.B10 Idd9.3 mice. Thus, Idd9.3‐encoded miR‐34a is a likely candidate in negatively regulating B‐cell lymphopoiesis, which may contribute to inefficient expansion of islet‐specific CD4+ T cells and to T1D protection in NOD.B10 Idd9.3 mice. 相似文献
8.
Myelin oligodendrocyte glycoprotein induces incomplete tolerance of CD4+ T cells specific for both a myelin and a neuronal self‐antigen in mice
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Liliana E. Lucca Pierre‐Paul Axisa Meryem Aloulou Corine Perals Abdulraouf Ramadan Pierre Rufas Bruno Kyewski Jens Derbinski Nicolas Fazilleau Lennart T. Mars Roland S. Liblau 《European journal of immunology》2016,46(9):2247-2259
T‐cell polyspecificity, predicting that individual T cells recognize a continuum of related ligands, implies that multiple antigens can tolerize T cells specific for a given self‐antigen. We previously showed in C57BL/6 mice that part of the CD4+ T‐cell repertoire specific for myelin oligodendrocyte glycoprotein (MOG) 35–55 also recognizes the neuronal antigen neurofilament medium (NF‐M) 15–35. Such bi‐specific CD4+ T cells are frequent and produce inflammatory cytokines after stimulation. Since T cells recognizing two self‐antigens would be expected to be tolerized more efficiently, this finding prompted us to study how polyspecificity impacts tolerance. We found that similar to MOG, NF‐M is expressed in the thymus by medullary thymic epithelial cells, a tolerogenic population. Nevertheless, the frequency, phenotype, and capacity to transfer experimental autoimmune encephalomyelitis (EAE) of MOG35‐55‐reactive CD4+ T cells were increased in MOG‐deficient but not in NF‐M‐deficient mice. We found that presentation of NF‐M15‐35 by I‐Ab on dendritic cells is of short duration, suggesting unstable MHC class II binding. Consistently, introducing an MHC‐anchoring residue into NF‐M15‐35 (NF‐M15‐35T20Y) increased its immunogenicity, activating a repertoire able to induce EAE. Our results show that in C57BL/6 mice bi‐specific encephalitogenic T cells manage to escape tolerization due to inefficient exposure to two self‐antigens. 相似文献
9.
Hisakata Yamada Kensuke Shibata Koji Sakuraba Kenjiro Fujimura Yasunobu Yoshikai 《European journal of immunology》2013,43(8):2033-2042
In contrast to thymic epithelial cells, which induce the positive selection of conventional CD8+ T cells, hematopoietic cells (HCs) select innate CD8+ T cells whose Ag specificity is not fully understood. Here we show that CD8+ T cells expressing an H‐Y Ag‐specific Tg TCR were able to develop in mice in which only HCs expressed MHC class I, when HCs also expressed the H‐Y Ag. These HC‐selected self‐specific CD8+ T cells resemble innate CD8+ T cells in WT mice in terms of the expression of memory markers and effector functions, but are phenotypically distinct from the thymus‐independent CD8+ T‐cell population. The peripheral maintenance of H‐Y‐specific CD8+ T cells required presentation of the self‐Ag and IL‐15 on HCs. HC‐selected CD8+ T cells in mice lacking the Tg TCR also showed these features. Furthermore, by using MHC class I tetramers with a male Ag peptide, we found that self‐Ag‐specific CD8+ T cells in TCR non‐Tg mice could develop via HC‐induced positive selection, supporting results obtained from H‐Y TCR Tg mice. These findings indicate the presence of self‐specific CD8+ T cells that are positively selected by HCs in the peripheral T‐cell repertoire. 相似文献
10.
Stimulation through very late antigen‐4 and ‐5 improves the multifunctionality and memory formation of CD8+ T cells
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Hayato Hosoi Hiroaki Ikeda Naoko Imai Chisaki Amaike Linan Wang Yuki Orito Makiko Yamane Hiroaki Ueno Mitsuko Ideno Ikuei Nukaya Tatsuji Enoki Junichi Mineno Kazutoh Takesako Satoshi Hirano Hiroshi Shiku 《European journal of immunology》2014,44(6):1747-1758
T cells express multiple integrin molecules. The significance of signaling through these molecules on acquisition of T‐cell effector functions and memory formation capacity remains largely unknown. Moreover, the impact of stimulation through these signals on the generation of T cells for adoptive immunotherapy has not been elucidated. In this study, using a recombinant fragment of fibronectin, CH‐296, we demonstrated that stimulation via very late Ag (VLA)‐4 and VLA‐5 in human and BALB/c mouse CD8+ T cells, in combination with TCR stimulation, enhances effector multifunctionality and in vivo memory formation. Using TCR‐transgenic mouse‐derived CD8+ T cells expressing TCR specific for the syngeneic CMS5 fibrosarcoma‐derived tumor Ag, we showed that stimulation by CH‐296 improved the ability of tumor‐specific CD8+ T cells to inhibit CMS5 tumor growth when adoptively transferred into hosts with progressing tumors. Improved antitumor effects were associated with decreased infiltration of Foxp3+CD4+ Treg cells in tumors. These results suggest that stimulation via VLA‐4 and VLA‐5 modulates the qualities of effector T cells and could potentially increase the efficacy of adoptive therapy against cancer. 相似文献
11.
Islet-reactive memory CD4+ T cells are an essential feature of type 1 diabetes (T1D) as they are involved in both spontaneous disease and in its recurrence after islet transplantation. Expansion and enrichment of memory T cells have also been shown in the peripheral blood of diabetic patients. Here, using high-throughput sequencing, we investigated the clonal diversity of the TCRβ repertoire of memory CD4+ T cells in the pancreatic lymph nodes (PaLN) of non-obese diabetic (NOD) mice and examined their clonal overlap with islet-infiltrating memory CD4 T cells. Both prediabetic and diabetic NOD mice exhibited a restricted TCRβ repertoire dominated by clones expressing TRBV13-2, TRBV13-1 or TRBV5 gene segments. There is a limited degree of TCRβ overlap between the memory CD4 repertoire of PaLN and pancreas as well as between the prediabetic and diabetic group. However, public TCRβ clonotypes were identified across several individual animals, some of them with sequences similar to the TCRs from the islet-reactive T cells suggesting their antigen-driven expansion. Moreover, the majority of the public clonotypes expressed TRBV13-2 (Vβ8.2) gene segment. Nasal vaccination with an immunodominat peptide derived from the TCR Vβ8.2 chain led to protection from diabetes, suggesting a critical role for Vβ8.2+ CD4+ memory T cells in T1D. These results suggest that memory CD4+ T cells bearing limited dominant TRBV genes contribute to the autoimmune diabetes and can be potentially targeted for intervention in diabetes. Furthermore, our results have important implications for the identification of public T cell clonotypes as potential novel targets for immune manipulation in human T1D. 相似文献
12.
CD40‐mediated signalling influences trafficking,T‐cell receptor expression,and T‐cell pathogenesis,in the NOD model of type 1 diabetes
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《Immunology》2017,152(2):243-254
CD40 plays a critical role in the pathogenesis of type 1 diabetes (T1D). The mechanism of action, however, is undetermined, probably because CD40 expression has been grossly underestimated. CD40 is expressed on numerous cell types that now include T cells and pancreatic β cells. CD40+ CD4+ cells [T helper type 40 (TH40)] prove highly pathogenic in NOD mice and in translational human T1D studies. We generated BDC2.5.CD40−/− and re‐derived NOD.CD154−/− mice to better understand the CD40 mechanism of action. Fully functional CD40 expression is required not only for T1D development but also for insulitis. In NOD mice, TH40 cell expansion in pancreatic lymph nodes occurs before insulitis and demonstrates an activated phenotype compared with conventional CD4+ cells, apparently regardless of antigen specificity. TH40 T‐cell receptor (TCR) usage demonstrates increases in several Vα and Vβ species, particularly Vα3.2+ that arise early and are sustained throughout disease development. TH40 cells isolated from diabetic pancreas demonstrate a relatively broad TCR repertoire rather than restricted clonal expansions. The expansion of the Vα/Vβ species associated with diabetes depends upon CD40 signalling; NOD.CD154−/− mice do not expand the same TCR species. Finally, CD40‐mediated signals significantly increase pro‐inflammatory Th1‐ and Th17‐associated cytokines whereas CD28 co‐stimulus alternatively promotes regulatory cytokines. 相似文献
13.
Generation of β cell‐specific human cytotoxic T cells by lentiviral transduction and their survival in immunodeficient human leucocyte antigen‐transgenic mice
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J. Babad G. Mukherjee A. Follenzi R. Ali B. O. Roep L. D. Shultz P. Santamaria O. O. Yang H. Goldstein D. L. Greiner T. P. DiLorenzo 《Clinical and experimental immunology》2015,179(3):398-413
Several β cell antigens recognized by T cells in the non‐obese diabetic (NOD) mouse model of type 1 diabetes (T1D) are also T cell targets in the human disease. While numerous antigen‐specific therapies prevent diabetes in NOD mice, successful translation of rodent findings to patients has been difficult. A human leucocyte antigen (HLA)‐transgenic mouse model incorporating human β cell‐specific T cells might provide a better platform for evaluating antigen‐specific therapies. The ability to study such T cells is limited by their low frequency in peripheral blood and the difficulty in obtaining islet‐infiltrating T cells from patients. We have worked to overcome this limitation by using lentiviral transduction to ‘reprogram’ primary human CD8 T cells to express three T cell receptors (TCRs) specific for a peptide derived from the β cell antigen islet‐specific glucose‐6‐phosphatase catalytic subunit‐related protein (IGRP265–273) and recognized in the context of the human class I major histocompatibility complex (MHC) molecule HLA‐A2. The TCRs bound peptide/MHC multimers with a range of avidities, but all bound with at least 10‐fold lower avidity than the anti‐viral TCR used for comparison. One exhibited antigenic recognition promiscuity. The β cell‐specific human CD8 T cells generated by lentiviral transduction with one of the TCRs released interferon (IFN)‐γ in response to antigen and exhibited cytotoxic activity against peptide‐pulsed target cells. The cells engrafted in HLA‐A2‐transgenic NOD‐scid IL2rγnull mice and could be detected in the blood, spleen and pancreas up to 5 weeks post‐transfer, suggesting the utility of this approach for the evaluation of T cell‐modulatory therapies for T1D and other T cell‐mediated autoimmune diseases. 相似文献
14.
15.
High‐throughput sequencing of TCR repertoires in multiple sclerosis reveals intrathecal enrichment of EBV‐reactive CD8+ T cells
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Andreas Lossius Jorunn N. Johansen Frode Vartdal Harlan Robins Benth Jūratė Šaltytė Johanna Olweus 《European journal of immunology》2014,44(11):3439-3452
Epstein‐Barr virus (EBV) has long been suggested as a pathogen in multiple sclerosis (MS). Here, we used high‐throughput sequencing to determine the diversity, compartmentalization, persistence, and EBV‐reactivity of the T‐cell receptor (TCR) repertoires in MS. TCR‐β genes were sequenced in paired samples of cerebrospinal fluid (CSF) and blood from patients with MS and controls with other inflammatory neurological diseases. The TCR repertoires were highly diverse in both compartments and patient groups. Expanded T‐cell clones, represented by TCR‐β sequences >0.1%, were of different identity in CSF and blood of MS patients, and persisted for more than a year. Reference TCR‐β libraries generated from peripheral blood T cells reactive against autologous EBV‐transformed B cells were highly enriched for public EBV‐specific sequences and were used to quantify EBV‐reactive TCR‐β sequences in CSF. TCR‐β sequences of EBV‐reactive CD8+ T cells, including several public EBV‐specific sequences, were intrathecally enriched in MS patients only, whereas those of EBV‐reactive CD4+ T cells were also enriched in CSF of controls. These data provide evidence for a clonally diverse, yet compartmentalized and persistent, intrathecal T‐cell response in MS. The presented strategy links TCR sequence to intrathecal T‐cell specificity, demonstrating enrichment of EBV‐reactive CD8+ T cells in MS. 相似文献
16.
17.
Detection of vasostatin‐1‐specific CD8+ T cells in non‐obese diabetic mice that contribute to diabetes pathogenesis
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E. Nikoopour O. Krougly E. Lee‐Chan S. M. Haeryfar B. Singh 《Clinical and experimental immunology》2016,185(3):292-300
Chromogranin A (ChgA) is an antigenic target of pathogenic CD4+ T cells in a non‐obese diabetic (NOD) mouse model of type 1 diabetes (T1D). Vasostatin‐1 is a naturally processed fragment of ChgA. We have now identified a novel H2‐Kd‐restricted epitope of vasostatin‐1, ChgA 36‐44, which elicits CD8+ T cell responses in NOD mice. By using ChgA 36‐44/Kd tetramers we have determined the frequency of vasostatin‐1‐specific CD8+ T cells in pancreatic islets and draining lymph nodes of NOD mice. We also demonstrate that vasostatin‐1‐specific CD4+ and CD8+ T cells constitute a significant fraction of islet‐infiltrating T cells in diabetic NOD mice. Adoptive transfer of T cells from ChgA 36‐44 peptide‐primed NOD mice into NOD/severe combined immunodeficiency (SCID) mice led to T1D development. These findings indicate that vasostatin‐1‐specific CD8+ T cells contribute to the pathogenesis of type 1 diabetes in NOD mice. 相似文献
18.
Oliver Schweier Ulrike Aichele Anna‐Friederike Marx Tobias Straub J. Sjef Verbeek Daniel D. Pinschewer Hanspeter Pircher 《European journal of immunology》2019,49(4):626-637
Infection of C57BL/6 mice with lymphocytic choriomeningitis virus (LCMV) strain Armstrong (Arm) induces an acute infection with rapid virus clearance by CD8+ T cells independently of CD4+ T cell help. Residual viral antigen may, however, persist for a prolonged time. Here, we demonstrate that mice that had been transiently depleted of CD4+ T cells during acute LCMV Arm infection generated high levels of virus‐specific IgG antibodies (Ab) after viral clearance. Robust induction of LCMV‐specific IgG after transient CD4+ T cell depletion was dependent on Fcγ receptors but not on the complement receptors CD21/CD35. In contrast to the potent production of LCMV‐specific IgG, the generation of LCMV‐specific isotype‐switched memory B cells after transient CD4+ T cell depletion was considerably reduced. Moreover, mice depleted of CD4+ T cells during acute infection were strongly impaired in generating a secondary LCMV‐specific B cell response upon LCMV rechallenge. In conclusion, our data indicate that LCMV antigen depots after viral clearance were capable of inducing high levels of virus‐specific IgG. They failed, however, to induce robust virus‐specific B cell memory revealing a previously unappreciated dichotomy of specific Ab production and memory cell formation after priming with residual antigen. 相似文献
19.
Gut commensal microbes do not represent a dominant antigenic source for continuous CD4+ T‐cell activation during HIV‐1 infection
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Kathrin Zimmermann Sonia Bastidas Leandra Knecht Herbert Kuster Stephan R. Vavricka Huldrych F. Günthard Annette Oxenius 《European journal of immunology》2015,45(11):3107-3113
Chronic immune activation is a hallmark of HIV‐1 infection; specifically, the activation of T cells has predictive value for progression to AIDS. The majority of hyperactivated T cells are not HIV‐specific and their antigenic specificities remain poorly understood. Translocation of gut luminal microbial products to systemic sites contributes to chronic immune activation during HIV‐1 infection, but how it affects (TCR‐dependent) immune activation remains elusive. We hypothesized that gut luminal antigens foster activation of CD4+ T cells with specificities for commensal bacterial antigens, thereby contributing to the pool of activated CD4+ T cells in the circulation of HIV‐1 infected individuals. To test this hypothesis, we quantified the frequencies of gut microbe‐specific CD4+ T cells by cytokine production upon restimulation with selected gut commensal microbial antigens. Contrary to our hypothesis, we did not observe increased but rather decreased frequencies of gut microbe‐specific CD4+ T cells in HIV‐1 infected individuals compared to healthy controls. We conclude that the increased activation status of circulating CD4+ T cells in HIV‐1 infected individuals is not driven by CD4+ T cells with specificities for commensal bacterial antigens. 相似文献
20.
Absence of both Sos‐1 and Sos‐2 in peripheral CD4+ T cells leads to PI3K pathway activation and defects in migration
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Geoffrey Guittard Robert L. Kortum Lakshmi Balagopalan Nicolas Çuburu Phan Nguyen Connie L. Sommers Lawrence E. Samelson 《European journal of immunology》2015,45(8):2389-2395
Sos‐1 and Sos‐2 are ubiquitously expressed Ras‐guanine exchange factors involved in Erk‐MAP kinase pathway activation. Using mice lacking genes encoding Sos‐1 and Sos‐2, we evaluated the role of these proteins in peripheral T‐cell signaling and function. Our results confirmed that TCR‐mediated Erk activation in peripheral CD4+ T cells does not depend on Sos‐1 and Sos‐2, although IL‐2‐mediated Erk activation does. Unexpectedly, however, we show an increase in AKT phosphorylation in Sos‐1/2dKO CD4+ T cells upon TCR and IL‐2 stimulation. Activation of AKT was likely a consequence of increased recruitment of PI3K to Grb2 upon TCR and/or IL‐2 stimulation in Sos‐1/2dKO CD4+ T cells. The increased activity of the PI3K/AKT pathway led to downregulation of the surface receptor CD62L in Sos‐1/2dKO T cells and a subsequent impairment in T‐cell migration. 相似文献