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1.
Dwivedi VP Tousif S Bhattacharya D Prasad DV Van Kaer L Das J Das G 《The Journal of biological chemistry》2012,287(5):2943-2947
TGF-β is a pleiotropic cytokine that predominantly exerts inhibitory functions in the immune system. Unexpectedly, the in vitro differentiation of both Th17 and Tc17 cells requires TGF-β. However, animals that are impaired in TGF-β signaling (TGF-βRIIDN mice) display multiorgan autoimmune disorders. Here we show that CD4(+) T cells from TGF-βRIIDN mice are resistant to Th17 cell differentiation and, paradoxically, that CD8(+) T cells from these animals spontaneously acquire an IL-17-producing phenotype. Neutralization of IL-17 or depletion of CD8(+) T cells dramatically inhibited inflammation in TGF-βRIIDN mice. Therefore, the absence of TGF-β triggers spontaneous differentiation of IL-17-producing CD8(+) T cells, suggesting that the in vivo and in vitro conditions that promote the differentiation of IL-17-producing CD8(+) T cells are distinct. 相似文献
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Villegas-Mendez A Greig R Shaw TN de Souza JB Gwyer Findlay E Stumhofer JS Hafalla JC Blount DG Hunter CA Riley EM Couper KN 《Journal of immunology (Baltimore, Md. : 1950)》2012,189(2):968-979
It is well established that IFN-γ is required for the development of experimental cerebral malaria (ECM) during Plasmodium berghei ANKA infection of C57BL/6 mice. However, the temporal and tissue-specific cellular sources of IFN-γ during P. berghei ANKA infection have not been investigated, and it is not known whether IFN-γ production by a single cell type in isolation can induce cerebral pathology. In this study, using IFN-γ reporter mice, we show that NK cells dominate the IFN-γ response during the early stages of infection in the brain, but not in the spleen, before being replaced by CD4(+) and CD8(+) T cells. Importantly, we demonstrate that IFN-γ-producing CD4(+) T cells, but not innate or CD8(+) T cells, can promote the development of ECM in normally resistant IFN-γ(-/-) mice infected with P. berghei ANKA. Adoptively transferred wild-type CD4(+) T cells accumulate within the spleen, lung, and brain of IFN-γ(-/-) mice and induce ECM through active IFN-γ secretion, which increases the accumulation of endogenous IFN-γ(-/-) CD8(+) T cells within the brain. Depletion of endogenous IFN-γ(-/-) CD8(+) T cells abrogates the ability of wild-type CD4(+) T cells to promote ECM. Finally, we show that IFN-γ production, specifically by CD4(+) T cells, is sufficient to induce expression of CXCL9 and CXCL10 within the brain, providing a mechanistic basis for the enhanced CD8(+) T cell accumulation. To our knowledge, these observations demonstrate, for the first time, the importance of and pathways by which IFN-γ-producing CD4(+) T cells promote the development of ECM during P. berghei ANKA infection. 相似文献
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Cutting edge: Generation of colitogenic Th17 CD4 T cells is enhanced by IL-17+ γδ T cells 总被引:1,自引:0,他引:1
Do JS Visperas A Dong C Baldwin WM Min B 《Journal of immunology (Baltimore, Md. : 1950)》2011,186(8):4546-4550
Th 17 cells have been implicated in the pathogenesis of colitis; however, a cellular mechanism by which colitogenic Th17 immunity arises in vivo remains unclear. In this study, we report that a subset of IL-17(+) γδ T cells plays a crucial role in enhancing in vivo Th17 differentiation and T cell-mediated colitis. TCRβ(-/-) mice were highly susceptible to T cell-mediated colitis, whereas TCRβδ(-/-) mice were resistant to the disease. Importantly, cotransfer of IL-17(+) but not of IL-17(-) γδ T cells with CD4 T cells was sufficient to enhance Th17 differentiation and induce full-blown colitis in TCRβδ(-/-) recipients. Collectively, our results provide a novel function of IL-17(+) γδ T cell subsets in supporting in vivo Th17 differentiation and possibly in fostering the development of intestinal inflammation. 相似文献
4.
A proportional balance between αβ and γδ T-cell subsets in the periphery is exceedingly well maintained by a homeostatic mechanism. However, a cellular mechanism underlying the regulation remains undefined. We recently reported that a subset of developing γδ T cells spontaneously acquires interleukin (IL)-17-producing capacity even within naive animals through a transforming growth factor (TGF)β1-dependent mechanism, thus considered 'innate' IL-17-producing cells. Here, we report that γδ T cells generated within αβ T cell (or CD4 T cell)-deficient environments displayed altered cytokine profiles; particularly, 'innate' IL-17 expression was significantly impaired compared with those in wild-type mice. Impaired IL-17 production in γδ T cells was directly related to CD4 T-cell deficiency, because depletion of CD4 T cells in wild-type mice diminished and adoptive CD4 T-cell transfer into T-cell receptor β-/- mice restored IL-17 expression in γδ T cells. CD4 T cell-mediated IL-17 expression required TGFβ1. Moreover, Th17 but not Th1 or Th2 effector CD4 T cells were highly efficient in enhancing γδ T-cell IL-17 expression. Taken together, our results highlight a novel CD4 T cell-dependent mechanism that shapes the generation of IL-17+ γδ T cells in naive settings. 相似文献
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Kochetkova I Thornburg T Callis G Pascual DW 《Journal of immunology (Baltimore, Md. : 1950)》2011,187(9):4654-4666
Oral immunization with a Salmonella vaccine vector expressing enterotoxigenic Escherichia coli colonization factor Ag I (CFA/I) can protect against collagen-induced arthritis (CIA) by dampening IL-17 and IFN-γ via enhanced IL-4, IL-10, and TGF-β. To identify the responsible regulatory CD4(+) T cells making the host refractory to CIA, Salmonella-CFA/I induced CD39(+)CD4(+) T cells with enhanced apyrase activity relative to Salmonella vector-immunized mice. Adoptive transfer of vaccine-induced CD39(+)CD4(+) T cells into CIA mice conferred complete protection, whereas CD39(-)CD4(+) T cells did not. Subsequent analysis of vaccinated Foxp3-GFP mice revealed the CD39(+) T cells were composed of Foxp3-GFP(-) and Foxp3-GFP(+) subpopulations. Although each adoptively transferred Salmonella-CFA/I-induced Foxp3(-) and Foxp3(+)CD39(+)CD4(+) T cells could protect against CIA, each subset was not as efficacious as total CD39(+)CD4(+) T cells, suggesting their interdependence for optimal protection. Cytokine analysis revealed Foxp3(-) CD39(+)CD4(+) T cells produced TGF-β, and Foxp3(+)CD39(+)CD4(+) T cells produced IL-10, showing a segregation of function. Moreover, donor Foxp3-GFP(-) CD4(+) T cells converted to Foxp3-GFP(+) CD39(+)CD4(+) T cells in the recipients, showing plasticity of these regulatory T cells. TGF-β was found to be essential for protection because in vivo TGF-β neutralization reversed activation of CREB and reduced the development of CD39(+)CD4(+) T cells. Thus, CD39 apyrase-expressing CD4(+) T cells stimulated by Salmonella-CFA/I are composed of TGF-β-producing Foxp3(-) CD39(+)CD4(+) T cells and support the stimulation of IL-10-producing Foxp3(+) CD39(+)CD4(+) T cells. 相似文献
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Takeshi Nitta Ryunosuke Muro Yukiko Shimizu Sachiko Nitta Hiroyo Oda Yuki Ohte Motohito Goto Rieko Yanobu-Takanashi Tomoya Narita Hiroshi Takayanagi Hisataka Yasuda Tadashi Okamura Shigeo Murata Harumi Suzuki 《EMBO reports》2015,16(5):638-653
The thymus provides a specialized microenvironment in which distinct subsets of thymic epithelial cells (TECs) support T-cell development. Here, we describe the significance of cortical TECs (cTECs) in T-cell development, using a newly established mouse model of cTEC deficiency. The deficiency of mature cTECs caused a massive loss of thymic cellularity and impaired the development of αβT cells and invariant natural killer T cells. Unexpectedly, the differentiation of certain γδT-cell subpopulations—interleukin-17-producing Vγ4 and Vγ6 cells—was strongly dysregulated, resulting in the perturbation of γδT-mediated inflammatory responses in peripheral tissues. These findings show that cTECs contribute to the shaping of the TCR repertoire, not only of “conventional” αβT cells but also of inflammatory “innate” γδT cells. 相似文献
9.
探讨外周血CD4~+、CD8~+T水平与慢性乙型肝炎不同中医体质的关系。选取2016年2月至2017年3月在我院治疗的慢性乙型感染患者143例,其中平和质35例、气虚质40例、阴虚质21例、湿热质20例,气郁质16例、其他11例,采用流式细胞仪检测外周血T淋巴细胞亚群。不同中医体质患者性别、年龄、病程及HBV-DNA含量比较差异无统计学意义(p0.05);平和质患者AST为342.21(142.42,513.46)U/L,明显低于其他患者(p0.05);气虚质患者AST为512.40(322.81,726.50)U/L,明显高于其他患者(p0.05);气郁质及其他体质患者ALT分别为381.64(210.41,501.72)U/L和370.43(200.41,470.63)U/L,明显高于平和质、气虚质、阴虚质和湿热质患者(p0.05);平和质和气虚质患者外周血CD4~+T细胞分别为(39.10±2.01)%和(39.10±2.01)%,明显低于阴虚质、湿热质、气郁质及其他体质患者(p0.05);气郁质及其他体质患者CD8~+T细胞分别为(25.43±1.33)%和(25.24±1.31)%,明显低于平和质、气虚质、阴虚质和湿热质患者(p0.05);阴虚质、气郁质及其他体质患者分别为(1.71±0.09)、(1.75±0.08)和(1.78±0.09),明显高于平和质、气虚质和湿热质患者(p0.05)。慢性乙肝不同中医体质与CD4~+T、CD8~+T和以及肝功能有密切关系。关键词 相似文献
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Aging is associated with a decline in immune function. Interferon-gamma (IFN-gamma) and interleukin-4 (IL-4), two important immune deviation-related cytokines, are mainly produced by type 1 and type 2 T cells, respectively. To investigate the age-associated changes in the secretion of these two cytokines, 20 elderly and 20 young subjects fulfilling the SENIEUR protocol were enrolled. The ratios of CD4+ to CD8+ T cells were not different between the two age groups. The CD4+ and CD8+ T cells were purified by a magnetic cell sorting system, and then activated by concurrent anti-CD3 and anti-CD28 stimulation. The released cytokines were determined by ELISA. Both the CD4+ and the CD8+ T cells of the elderly individuals secreted a significantly larger amount of IFN-gamma after activation. Profound IL-4 production by CD8+ T cells was observed in the older subjects compared with that of the young subjects. These data suggested that age-associated decrease in immunity may be related to an imbalance in the secretion of immune deviation cytokines. The number of IL-4-secreting CD8+ T cells (T cytotoxic 2) rose significantly in the older individuals. Our design also provided a useful way to differentiate the T cell subsets secreting the same cytokine, such as IFN-gamma-producing T helper 1 and T cytotoxic 1 cells. 相似文献
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Hua-xia Yang Wen Zhang Li-dan Zhao Yang Li Feng-chun Zhang Fu-lin Tang Wei He Xuan Zhang 《Arthritis research & therapy》2009,11(5):R153
Introduction
Our previous study has reported that, in patients with untreated new-onset lupus (UNOL), there was an abnormal increase in the number of CD4+CD25-Foxp3+ T cells that correlated with disease activity and significantly decreased after treatment. However, little is known about the nature of this cell entity. The aim of this study was to explore the nature of abnormally increased CD4+CD25-Foxp3+ T cells in UNOL patients. 相似文献13.
Altvater B Pscherer S Landmeier S Kailayangiri S Savoldo B Juergens H Rossig C 《Cancer immunology, immunotherapy : CII》2012,61(3):385-396
Specific cellular immunotherapy of cancer requires efficient generation and expansion of cytotoxic T lymphocytes (CTLs) that
recognize tumor-associated self-antigens. Here, we investigated the capacity of human γδ T cells to induce expansion of CD8+
T cells specific for peptides derived from the weakly immunogenic tumor-associated self-antigens PRAME and STEAP1. Coincubation
of aminobisphosphonate-stimulated human peripheral blood-derived γδ T cells (Vγ9+Vδ2+), loaded with HLA-A*02-restricted epitopes
of PRAME, with autologous peripheral blood CD8+ T cells stimulated the expansion of peptide-specific cytolytic effector memory
T cells. Moreover, peptide-loaded γδ T cells efficiently primed antigen-naive CD45RA+ CD8+ T cells against PRAME peptides.
Direct comparisons with mature DCs revealed equal potency of γδ T cells and DCs in inducing primary T-cell responses and peptide-specific
T-cell activation and expansion. Antigen presentation by γδ T-APCs was not able to overcome the limited capacity of peptide-specific
T cells to interact with targets expressing full-length antigen. Importantly, T cells with regulatory phenotype (CD4+CD25hiFoxP3+)
were lower in cocultures with γδ T cells compared to DCs. In summary, bisphosphonate-activated γδ T cells permit generation
of CTLs specific for weakly immunogenic tumor-associated epitopes. Exploiting this strategy for effective immunotherapy of
cancer requires strategies that enhance the avidity of CTL responses to allow for efficient targeting of cancer. 相似文献
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Noriyuki Hirata Yoshiki Yanagawa Masashi Satoh Takashi Ebihara Machiko Matsumoto Tsukasa Seya Kazuya Iwabuchi 《Cellular immunology》2010,261(1):37-41
Immature dendritic cells (DCs) appear to be involved in peripheral immune tolerance via induction of IL-10-producing CD4+ T cells. We examined the role of TNF-α in generation of the IL-10-producing CD4+ T cells by immature DCs. Immature bone marrow-derived DCs from wild type (WT) or TNF-α−/− mice were cocultured with CD4+ T cells from OVA specific TCR transgenic mice (OT-II) in the presence of OVA323-339 peptide. The WT DCs efficiently induced the antigen-specific IL-10-producing CD4+ T cells, while the ability of the TNF-α−/− DCs to induce these CD4+ T cells was considerably depressed. Addition of exogenous TNF-α recovered the impaired ability of the TNF-α−/− DCs to induce IL-10-producing T cells. However, no difference in this ability was observed between TNF-α−/− and WT DCs after their maturation by LPS. Thus, TNF-α appears to be critical for the generation of IL-10-producing CD4+ T cells during the antigen presentation by immature DCs. 相似文献
15.
Activated murine endothelial cells have reduced immunogenicity for CD8+ T cells: a mechanism of immunoregulation? 总被引:1,自引:0,他引:1
Marelli-Berg FM Scott D Bartok I Peek E Dyson J Lechler RI 《Journal of immunology (Baltimore, Md. : 1950)》2000,165(8):4182-4189
The immunogenic properties of primary cultures of murine lung microvascular endothelial cells (EC) were analyzed. Resting endothelial cells were found to constitutively express low levels of MHC class I and CD80 molecules. IFN-gamma treatment of EC resulted in a marked up-regulation of MHC class I, but no change was observed in the level of CD80 expression. No CD86 molecules were detectable under either condition. The ability of peptide-pulsed EC to induce the proliferation of either the HY-specific, H2-K(k)-restricted CD8(+) T cell clone (C6) or C6 TCR-transgenic naive CD8(+) T cells was analyzed. Resting T cells were stimulated to divide by quiescent peptide-prepulsed EC, while peptide-pulsed, cytokine-activated EC lost the ability to induce T cell division. Furthermore, Ag presentation by cytokine-activated EC induced CD8(+) T cell hyporesponsiveness. The immunogenicity of activated EC could be restored by adding nonsaturating concentrations of anti-H2-K(k) Ab in the presence of an optimal concentration of cognate peptide. This is consistent with the suggestion that the ratio of TCR engagement to costimulation determines the outcome of T cell recognition. In contrast, activated peptide-pulsed EC were killed more efficiently by fully differentiated effector CD8(+) T cells. Finally, evidence is provided that Ag recognition of EC can profoundly affect the transendothelial migration of CD8(+) T cells. Taken together, these results suggest that EC immunogenicity is regulated in a manner that contributes to peripheral tolerance. 相似文献
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Redouane Rouas Makram Merimi Mehdi Najar Nabil El Zein Mohammad Fayyad-Kazan Mimoune Berehab Douaa Agha Dominique Bron Arsene Burny Walid Rachidi Bassam Badran Philippe Lewalle Hussein Fayyad-Kazan 《Journal of cellular physiology》2019,234(10):17459-17472
Regulatory T cells (Tregs) are central for maintaining immune balance and their dysfunction drives the expansion of critical immunologic disorders. During the past decade, microRNAs (miRNAs) have emerged as potent regulators of gene expression among which immune-related genes and their immunomodulatory properties have been associated with different immune-based diseases. The miRNA signature of human peripheral blood (PB) CD8+CD25 +CD127 low Tregs has not been described yet. We thus identified, using TaqMan low-density array (TLDA) technique followed by individual quantitative real-time polymerase chain reaction (qRT-PCR) confirmation, 14 miRNAs, among which 12 were downregulated whereas two were upregulated in CD8 +CD25 +CD127 low Tregs in comparison to CD8 +CD25 − T cells. In the next step, microRNA Data Integration Portal (mirDIP) was used to identify potential miRNA target sites in the 3′-untranslated region (3′-UTR) of key Treg cell-immunomodulatory genes with a special focus on interleukin 10 (IL-10) and transforming growth factor β (TGF-β). Having identified potential miR target sites in the 3′-UTR of IL-10 (miR-27b-3p and miR-340-5p) and TGF-β (miR-330-3p), we showed through transfection and transduction assays that the overexpression of two underexpressed miRNAs, miR-27b-3p and miR-340-5p, downregulated IL-10 expression upon targeting its 3′-UTR. Similarly, overexpression of miR-330-3p negatively regulated TGF-β expression. These results highlighted an important impact of the CD8 + Treg mirnome on the expression of genes with significant implication on immunosuppression. These observations could help in better understanding the mechanism(s) orchestrating Treg immunosuppressive function toward unraveling new targets for treating autoimmune pathologies and cancer. 相似文献
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Hong-Ge Yang Yan-Mei Jiao Hui-Huang Huang Chao Zhang Ji-Yuan Zhang Ruo-Nan Xu Jin-Wen Song Xing Fan Lei Jin Ming Shi Fu-Sheng Wang 《Microbiology and immunology》2020,64(6):458-468
HIV replication can be inhibited by CXCR5+CD8 T cells (follicular cytotoxic T cell [TFC]) which transfer into B-cell follicles where latent HIV infection persists. However, how cytokines affect TFC remain unclear. Understanding which cytokines show the ability to affect TFC could be a key strategy toward curing HIV. Similar mechanisms could be used for the growth and transfer of TFCs and follicular helper T (TFH) cells; as a result, we hypothesized that cytokines IL-6, IL-21, and transforming growth factor-β (TGF-β), which are necessary for the differentiation of TFH cells, could also dictate the development of TFCs. In this work, lymph node mononuclear cells and peripheral blood mononuclear cells from HIV-infected individuals were cocultured with IL-6, IL-21, and TGF-β. We then carried out T-cell receptor (TCR) repertoire analysis to compare the differences between CXCR5– and CXCR5+CD8 T cells. Our results showed that the percentage and function of TFC can be enhanced by stimulation with TGF-β. Besides, TGF-β stimulation enhanced the diversity of TCR and complementarity-determining region 3 sequences. HIV DNA showed a negative correlation with TFC. The use of TGF-β to promote the expression of CXCR5+CD8 T cells could become a new treatment approach for curing HIV. 相似文献
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IL-22 is a novel cytokine in the IL-10 family that functions to promote innate immunity of tissues against infection. Although CD4+ helper T lymphocytes (TH) were found as a source of IL-22, the regulation of this cytokine has been poorly understood. Here, we show that IL-22 is expressed at both mRNA and protein levels by a novel subset of TH cells that also makes IL-17. IL-22 and IL-17 were found to be coordinately regulated by TGFI3 and IL-6 during TH differentiation by real-time PCR as well as ELISA analysis. However, IL-22 does not regulate TH differentiation; exogenous IL-22 or an IL-22 antagonist had no effect on TH differentiation. These data demonstrate a novel cytokine expressed by IL-17-producing T cells, and suggest interaction and synergy of IL-22 and IL-l 7 signaling pathways in tissue inflammation and autoimmune diseases. 相似文献