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1.
Kyoko Omi Masumi Shimizu Eri Watanabe Jiro Matsumura Chizuno Takaku Eiji Shinya Hidemi Takahashi 《Immunology》2014,141(4):596-608
After the development of highly active anti‐retroviral therapy, it became clear that the majority of emergent HIV‐1 is macrophage‐tropic and infects CD4+, CCR5‐expressing cells (R5‐tropic). There are three distinct cell populations, R5‐tropic, HIV‐1‐susceptible CD4+ cells: (i) natural killer T (NKT) cells, (ii) dendritic cells and macrophages, and (iii) tissue‐associated T cells residing primarily at mucosal surfaces. We have confirmed that CD4+ NKT cells derived from peripheral blood mononuclear cells (PBMCs) predominantly express CCR5 rather than CXCR4, whereas the reverse is true for CD4+ T cells derived from circulating PBMCs, and that R5‐tropic HIV‐1 expands efficiently in the CD4+ NKT cells. Moreover, when PBMCs depleted of CD8α+ cells were stimulated in the presence of α‐galactosylceramide (α‐GalCer) and R5‐tropic HIV‐1 [NL(AD8)], the production of HIV‐1 virions was not suppressed, whereas, similar to the untreated PBMCs, depletion of CD8β+ cells from PBMCs significantly inhibited virion production. These findings suggest that CD8αα+ but not CD8αβ+ cells may have the ability to inhibit R5‐tropic HIV‐1 replication in CD4+ NKT cells. Here, we show that co‐culturing R5‐tropic HIV‐1‐infected CD4+ NKT cells with CD8αα+ γδ T cells, in particular Vγ1Vδ1 cells, but not with CD8αα+ NKT cells or CD8αα+ dendritic cells, inhibits HIV‐1 replication mainly by secreting chemokines, such as macrophage inflammatory proteins 1α and 1β and RANTES. Collectively, these results indicate the importance of CD8αα+ γδ T cells in the control of R5‐tropic HIV‐1 replication and persistence in CD4+ NKT cells. 相似文献
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IFN‐γ‐producing NKT cells exacerbate sepsis by enhancing C5a generation via IL‐10‐mediated inhibition of CD55 expression on neutrophils
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Ji Hyung Kim Sae Jin Oh Sehee Ahn Doo Hyun Chung 《European journal of immunology》2014,44(7):2025-2035
A role for NKT cells has been implicated in sepsis, but the mechanism by which NKT cells contribute to sepsis remains unclear. Here, we examined WT and NKT‐cell‐deficient mice of C57BL/6 background during cecal ligation and puncture‐induced sepsis. The levels of C5a, IFN‐γ, and IL‐10 were higher in the serum and peritoneal fluid of WT mice than in those of CD1d?/? mice, while the mortality rate was lower in CD1d?/? mice than in WT mice. C5a blockade decreased mortality of WT mice during sepsis, whereas it did not alter that of CD1d?/? mice. As assessed by intracellular staining, NKT cells expressed IFN‐γ, while neutrophils expressed IL‐10. Upon coculture, IL‐10‐deficient NKT cells enhanced IL‐10 production by WT, but not IFN‐γR‐deficient, neutrophils. Meanwhile, CD1d?/? mice exhibited high CD55 expression on neutrophils during sepsis, whereas those cells from WT mice expressed minimal levels of CD55. Recombinant IL‐10 administration into CD1d?/? mice reduced CD55 expression on neutrophils. Furthermore, adoptive transfer of sorted WT, but not IFN‐γ‐deficient, NKT cells into CD1d?/? mice suppressed CD55 expression on neutrophils, but increased IL‐10 and C5a levels. Taken together, IFN‐γ‐producing NKT cells enhance C5a generation via IL‐10‐mediated inhibition of CD55 expression on neutrophils, thereby exacerbating sepsis. 相似文献
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Yein‐Gei Lai Mau‐Sheng Hou Albert Lo Shih‐Ting Huang Yen‐Wen Huang Hsin‐Fang Yang‐Yen Nan‐Shih Liao 《European journal of immunology》2013,43(9):2305-2316
IL‐15 is an essential survival factor for CD8αα+ intestinal intraepithelial lymphocytes (iIELs) in vitro and in vivo. However, the IL‐15‐induced survival signals in primary CD8αα+ iIELs remains elusive. Although Bcl‐2 level in CD8αα+ iIELs positively correlates with IL‐15Rα expression in the intestinal epithelial cells, overexpression of Bcl‐2 only moderately restores CD8αα+ γδ iIELs in Il15?/? mice. Here, we found that IL‐15 promptly activated a Jak3‐Jak1‐PI3K‐Akt pathway that led to the upregulation of Bcl‐2 and Mcl‐1. This pathway also induced a delayed but sustained ERK1/2 activation, which not only was necessary for the maintenance of Bcl‐2 but also resulted in the phosphorylation of extra‐long Bim at Ser65. The latter event facilitated the dissociation of Bim from Bcl‐2 without affecting Bim abundance in IL‐15‐treated CD8αα+ iIELs. Using an adoptive cell transfer approach, we found that either overexpression of Bcl‐2 or removal of Bim from CD8αα+ iIELs promoted their survival in Il15ra?/? mice. Taken together, IL‐15 promotes CD8αα+ iIEL survival by both increasing Bcl‐2 levels and dissociating Bim from Bcl‐2 through activation of a Jak3‐Jak1‐PI3K‐Akt‐ERK1/2 pathway, which differs from a previously reported IL‐15‐induced survival signal. 相似文献
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Syndecan‐1 identifies and controls the frequency of IL‐17‐producing naïve natural killer T (NKT17) cells in mice
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Hong Dai Ayesha Rahman Ankit Saxena Anil K Jaiswal Abdiaziz Mohamood Lourdes Ramirez Sanjeev Noel Hamid Rabb Chunfa Jie Abdel Rahim A Hamad 《European journal of immunology》2015,45(11):3045-3051
Invariant natural killer T (iNKT) cells recognize glycolipids as antigens and diversify into NKT1 (IFN‐γ), NKT2 (IL‐4), and NKT17 (IL‐17) functional subsets while developing in the thymus. Mechanisms that govern the balance between these functional subsets are poorly understood due, partly, to the lack of distinguishing surface markers. Here we identify the heparan sulfate proteoglycan syndecan‐1 (sdc1) as a specific marker of naïve thymic NKT17 cells in mice and show that sdc1 deficiency significantly increases thymic NKT17 cells at the expense of NKT1 cells, leading to impaired iNKT cell‐derived IFN‐γ, both in vitro and in vivo. Using surface expression of sdc1 to identify NKT17 cells, we confirm differential tissue localization and interstrain variability of NKT17 cells, and reveal that NKT17 cells express high levels of TCR‐β, preferentially use Vβ8, and are more highly sensitive to ɑ‐GalCer than to CD3/CD28 stimulation. These findings provide a novel, noninvasive, simple method for identification, and viable sorting of naïve NKT17 cells from unmanipulated mice, and suggest that sdc1 expression negatively regulates homeostasis in iNKT cells. In addition, these findings lay the groundwork for investigating the mechanisms by which sdc1 regulates NKT17 cells. 相似文献
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Armelle Regnault Jean-Pierre Levraud Annick Lim Adrien Six Christiane Moreau Ana Cumano Philippe Kourilsky 《European journal of immunology》1996,26(4):914-921
In conventional mice, the T cell receptor (TCR)αβ+ CD8αα+ and CD8αβ+ subsets of the intestinal intraepithelial lymphocytes (IEL) constitute two subpopulations. Each comprise a few hundred clones expressing apparently random receptor repertoires which are different in individual genetically identical mice (Regnault, A., Cumano, A., Vassalli, P., Guy-Grand, D. and Kourilsky, P., J. Exp. Med. 1994. 180: 1345). We analyzed the repertoire diversity of sorted CD8αα and CD8αβ+ IEL populations from the small intestine of individual germ-free mice that contain ten times less TCRαβ+ T cells than conventional mice. The TCRβ repertoire of the CD8αα and the CD8αβ IEL populations of germ-free adult mice shows the same degree of oligoclonality as that of conventional mice. These results show that the intestinal microflora is not responsible for the repertoire oligoclonality of TCRαβ+ IEL. The presence of the microflora leads to an expansion of clones which arise independently of bacteria. To evaluate the degree of expansion of IEL clones in conventional mice, we went on to measure their clone sizes in vivo by quantitative PCR in the total and in adjacent sections of the small intestine of adult animals. We found that both the CD8αα and the CD8αβ TCRαβ IEL clones have a heterogeneous size pattern, with clones containing from 3 × 103 cells up to 1.2 × 106 cells, the clones being qualitatively and quantitatively different in individual mice. Cells from a given IEL clone are not evenly distributed throughout the length of the small intestine. The observation that the TCRαβ IEL populations comprise a few hundred clones of very heterogeneous size and distribution suggests that they arise from a limited number of precursors, which may be slowly but continuously renewed, and undergo extensive clonal expansion in the epithelium. 相似文献
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Preferentially expanding Vγ1+ γδ T cells are associated with protective immunity against Plasmodium infection in mice
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Shin‐Ichi Inoue Mamoru Niikura Hiroko Asahi Yoichiro Iwakura Yasushi Kawakami Fumie Kobayashi 《European journal of immunology》2017,47(4):685-691
γδ T cells play a crucial role in controlling malaria parasites. Dendritic cell (DC) activation via CD40 ligand (CD40L)‐CD40 signaling by γδ T cells induces protective immunity against the blood‐stage Plasmodium berghei XAT (PbXAT) parasites in mice. However, it is unknown which γδ T‐cell subset has an effector role and is required to control the Plasmodium infection. Here, using antibodies to deplete TCR Vγ1+ cells, we saw that Vγ1+ γδ T cells were important for the control of PbXAT infection. Splenic Vγ1+ γδ T cells preferentially expand and express CD40L, and both Vγ1+ and Vγ4+ γδ T cells produce IFN‐γ during infection. Although expression of CD40L on Vγ1+ γδ T cells is maintained during infection, the IFN‐γ positivity of Vγ1+ γδ T cells is reduced in late‐phase infection due to γδ T‐cell dysfunction. In Plasmodium‐infected IFN‐γ signaling‐deficient mice, DC activation is reduced, resulting in the suppression of γδ T‐cell dysfunction and the dampening of γδ T‐cell expansion in the late phase of infection. Our data suggest that Vγ1+ γδ T cells represent a major subset responding to PbXAT infection and that the Vγ1+ γδ T‐cell response is dependent on IFN‐γ‐activated DCs. 相似文献
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CD4+Foxp3+ Treg maintain peripheral tolerance and influence immune responses to foreign antigens. The thymus is an important source of Treg, but controversy exists as to whether T cells are selected into the Treg lineage based on signals received through TCR specific for self‐peptides. To examine the specificity of TCR expressed by Treg and its effect on CD4+ T‐cell development, we generated Treg‐TCR transgenic mice. Deletion of >90% of CD4+ T cells in RAG‐sufficient mice, and nearly 100% deletion in RAG?/? mice expressing this TCR indicate that the TCR is specific for an unknown, naturally expressed peptide in the thymus. Deletion occurs late in development, suggesting this peptide is presented by APC in the thymic medulla. These studies are the first to describe the effects of expressing a Treg‐TCR on CD4+ T‐cell development. The implications of our data for models of Treg selection are discussed. 相似文献
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Emma M. Salisbury Lihui Wang Onjee Choi Sophie Rutschmann Philip G. Ashton‐Rickardt 《Immunology》2014,141(3):446-456
Natural regulatory T (nTreg) cells generated in the thymus are essential throughout life for the maintenance of T‐cell homeostasis and the prevention of autoimmunity. T‐cell receptor (TCR)/CD28‐mediated activation of nuclear factor‐κB and (J)un (N)‐terminal kinase pathways is known to play a key role in nTreg cell development but many of the predicted molecular interactions are based on extrapolations from non‐Treg cell TCR stimulation with non‐physiological ligands. For the first time, we provide strong genetic evidence of a scaffold function for the Caspase Recruitment Domain (CARD) of the TCR signalling protein CARD‐MAGUK1 (CARMA1) in nTreg cell development in vivo. We report two, new, N‐ethyl‐N‐nitrosourea‐derived mutant mice, Vulpo and Zerda, with a profound block in the development of nTreg cells in the thymus as well as impaired inducible Treg cell differentiation in the periphery. Despite independent heritage, both mutants harbour different point mutations in the CARD of the CARMA1 protein. Mutations in vulpo and zerda do not affect expression levels of CARMA1 but still impair signalling through the TCR due to defective downstream Bcl‐10 recruitment by the mutated CARD of CARMA1. Phenotypic differences observed between Vulpo and Zerda mutants suggest a role for the CARD of CARMA1 independent of Bcl‐10 activation of downstream pathways. We conclude that our forward genetic approach demonstrates a critical role for the CARD function of CARMA1 in Treg cell development in vivo. 相似文献
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We vaccinated mice with DC loaded with or without invariant NKT‐cell ligand α‐galactosylceramide and evaluated long‐term resistance against tumor challenge. When mice had been given either DC or DC/galactosylceramide and were challenged with tumor cells even 6–12 months later, both NK and NKT cells were quickly activated to express CD69 and produce IFN‐γ. The NK cells could resist a challenge with several different tumors in vivo. The activated NK and NKT cells could be depleted with anti‐NK1.1 treatment. In spite of this, the activated cells recovered, indicating that tumor‐responsive NK and NKT cells were being generated continuously as a result of vaccination with DC and were not true memory cells. The NK and NKT antitumor response in DC‐vaccinated mice depended on CD4+ T cells, but neither CD8+T cells nor CD4+CD25+ regulatory T cells. However, both vaccine DC and host DC were required for the development of long‐term, tumor reactive innate immunity. These results indicate that DC therapy in mice induces long‐lasting innate NK‐ and NKT‐cell activation through a pathway that requires host DC and CD4+ T cells and that the continued generation of active NK cells resists the establishment of metastases in vivo. 相似文献
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Daniel Brndle Karin Brduscha-Riem Adrian C. Hayday Michael J. Owen Hans Hengartner Hanspeter Pircher 《European journal of immunology》1995,25(9):2650-2655
We examined T cell development and T cell repertoire in transgenic mice expressing a single T cell receptor (TCR) α chain derived from the H-2Db -lymphocytic choriomeningitis virus (LCMV)-specific cytolytic T lymphocyte (CTL) clone P14. To generate these α P14 mice, mice transgenic for the P14 TCR α chain were backcrossed to TCR α-deficient mice. Thymi from α P14 mice exhibited a marked decrease of mature CD4+8? and CD8+4? single-positive thymocytes comparable to thymi from TCR α-deficient mice. Correspondingly, the number of peripheral T cells was reduced in the CD4 (tenfold) and in the CD8 (twofold) subsets when compared to normal mice. T cells from α P14 mice generated a primary anti-LCMV CTL response when stimulated in vitro with LCMV in contrast to normal mice which require priming in vivo; elimination of LCMV in vivo was, however, not improved. Flow cytometric analysis of T cells with Vβ-specific antibodies showed a diverse endogenous TCR Vβ repertoire. Functional analysis of the T cell repertoire, however, revealed a strongly reduced (30-fold) allogeneic and the absence of a vesicular stomatitis virus-specific CTL response and an impaired ability to provide T cell help for antibody isotype switching. Thus, T cell selection in the thymus was impaired and the T cell repertoire was limited in mice expressing only one type of TCR α chain. 相似文献
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Hartmann Raifer Azita J. Mahiny Nadine Bollig Franziska Petermann Anne Hellhund Kerstin Kellner Anna Guralnik Katharina Reinhard Evita Bothur Magdalena Huber Stefan Bauer Max Löhning Elina A. Kiss Stephanie C. Ganal Andreas Diefenbach Thomas Korn Michael Lohoff 《European journal of immunology》2012,42(12):3189-3201
16.
Commensal A4 bacteria inhibit intestinal Th2‐cell responses through induction of dendritic cell TGF‐β production
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Wei Wu Hou‐Pu Liu Feidi Chen Han Liu Anthony T. Cao Suxia Yao Mingming Sun Heather L. Evans‐Marin Ye Zhao Qing Zhao L. Wayne Duck Charles O. Elson Zhanju Liu Yingzi Cong 《European journal of immunology》2016,46(5):1162-1167
It has been shown that while commensal bacteria promote Th1, Th17 and Treg cells in lamina propria (LP) in steady‐state conditions, they suppress mucosal Th2 cells. However, it is still unclear whether there are specific commensal organisms down‐regulating Th2 responses, and the mechanism involved. Here we demonstrate that commensal A4 bacteria, a member of the Lachnospiraceae family, which produce an immunodominant microbiota CBir1 antigen, inhibits LP Th2‐cell development. When transferred into the intestines of RAG?/? mice, CBir1‐specific T cells developed predominately towards Th1 cells and Th17 cells, but to a lesser extent into Th2 cells. The addition of A4 bacterial lysates to CD4+ T‐cell cultures inhibited production of IL‐4. A4 bacteria stimulated dendritic cell production of TGF‐β, and blockade of TGF‐β abrogated A4 bacteria inhibition of Th2‐cell development in vitro and in vivo. Collectively, our data show that A4 bacteria inhibit Th2‐cell differentiation by inducing dendritic cell production of TGF‐β. 相似文献
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Allele‐sensitive mutant,Itkas, reveals that Itk kinase activity is required for Th1, Th2, Th17, and iNKT‐cell cytokine production
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Arun Kannan YongChan Lee Qian Qi Weishan Huang Ah‐Reum Jeong Sarah Ohnigian Avery August 《European journal of immunology》2015,45(8):2276-2285
Itk?/? mice exhibit defects in the activation, development, and function of CD4+ and CD8+ T cells and iNKT cells. These and other defects in these mice make it difficult to uncouple the developmental versus functional requirement of Itk signaling. Here, we report an allele‐sensitive mutant of Itk (Itkas) whose catalytic activity can be selectively inhibited by analogs of the PP1 kinase inhibitor. We show that Itkas behaves like WT Itk in the absence of the inhibitor and can rescue the development of Itk?/? T cells in mice. Using mice carrying Itkas, we show using its inhibitor that Itk activity is required not only for Th2, Th17, and iNKT‐cell cytokine production, but also surprisingly, for Th1 cytokine production. This work has important implications for understanding the role of Itk signaling in the development versus function of iNKT cells, Th1, Th2, and Th17 cells. 相似文献
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Protein tyrosine phosphatase PTPN22 regulates IL‐1β dependent Th17 responses by modulating dectin‐1 signaling in mice
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Harriet A Purvis Fiona Clarke Christine K Jordan Cristina Sanchez Blanco Georgina H Cornish Xuezhi Dai David J Rawlings Rose Zamoyska Andrew P Cope 《European journal of immunology》2018,48(2):306-315
A single nucleotide polymorphism within the PTPN22 gene is a strong genetic risk factor predisposing to the development of multiple autoimmune diseases. PTPN22 regulates Syk and Src family kinases downstream of immuno‐receptors. Fungal β‐glucan receptor dectin‐1 signals via Syk, and dectin‐1 stimulation induces arthritis in mouse models. We investigated whether PTPN22 regulates dectin‐1 dependent immune responses. Bone marrow derived dendritic cells (BMDCs) generated from C57BL/6 wild type (WT) and Ptpn22?/? mutant mice, were pulsed with OVA323‐339 and the dectin‐1 agonist curdlan and co‐cultured in vitro with OT‐II T‐cells or adoptively transferred into OT‐II mice, and T‐cell responses were determined by immunoassay. Dectin‐1 activated Ptpn22?/? BMDCs enhanced T‐cell secretion of IL‐17 in vitro and in vivo in an IL‐1β dependent manner. Immunoblotting revealed that compared to WT, dectin‐1 activated Ptpn22?/? BMDCs displayed enhanced Syk and Erk phosphorylation. Dectin‐1 activation of BMDCs expressing Ptpn22R619W (the mouse orthologue of human PTPN22R620W) also resulted in increased IL‐1β secretion and T‐cell dependent IL‐17 responses, indicating that in the context of dectin‐1 Ptpn22R619W operates as a loss‐of‐function variant. These findings highlight PTPN22 as a novel regulator of dectin‐1 signals, providing a link between genetically conferred perturbations of innate receptor signaling and the risk of autoimmune disease. 相似文献