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1.
Either IL-2 or IL-12 is sufficient to direct Th1 differentiation by nonobese diabetic T cells 总被引:5,自引:0,他引:5
Th cell differentiation from naive precursors is a tightly controlled process; the most critical differentiation factor is the action of the driving cytokine: IL-12 for Th1 development, IL-4 for Th2 development. We found that CD4(+) T cells from nonobese diabetic mice spontaneously differentiate into IFN-gamma-producing Th1 cells in response to polyclonal TCR stimulation in the absence of IL-12 and IFN-gamma. Instead, IL-2 was necessary and sufficient to direct T cell differentiation to the Th1 lineage by nonobese diabetic CD4(+) T cells. Its ability to direct Th1 differentiation of both naive and memory CD4(+) T cells was clearly uncoupled from its ability to stimulate cell division. Autocrine IL-2-driven Th1 differentiation of nonobese diabetic T cells may represent a genetic liability that favors development of IFN-gamma-producing autoreactive T cells. 相似文献
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N-acetylglucosaminyltransferase V (Mgat5)-mediated N-glycosylation negatively regulates Th1 cytokine production by T cells 总被引:4,自引:0,他引:4
Morgan R Gao G Pawling J Dennis JW Demetriou M Li B 《Journal of immunology (Baltimore, Md. : 1950)》2004,173(12):7200-7208
The differentiation of naive CD4(+) T cells into either proinflammatory Th1 or proallergic Th2 cells strongly influences autoimmunity, allergy, and tumor immune surveillance. We previously demonstrated that beta1,6GlcNAc-branched complex-type (N-acetylglucosaminyltransferase V (Mgat5)) N-glycans on TCR are bound to galectins, an interaction that reduces TCR signaling by opposing agonist-induced TCR clustering at the immune synapse. Mgat5(-/-) mice display late-onset spontaneous autoimmune disease and enhanced resistance to tumor progression and metastasis. In this study we examined the role of beta1,6GlcNAc N-glycan expression in Th1/Th2 cytokine production and differentiation. beta1,6GlcNAc N-glycan expression is enhanced by TCR stimulation independent of cell division and declines at the end of the stimulation cycle. Anti-CD3-activated splenocytes and naive T cells from Mgat5(-/-) mice produce more IFN-gamma and less IL-4 compared with wild-type cells, the latter resulting in the loss of IL-4-dependent down-regulation of IL-4Ralpha. Swainsonine, an inhibitor of Golgi alpha-mannosidase II, blocked beta1,6GlcNAc N-glycan expression and caused a similar increase in IFN-gamma production by T cells from humans and mice, but no additional enhancement in Mgat5(-/-) T cells. Mgat5 deficiency did not alter IFN-gamma/IL-4 production by polarized Th1 cells, but caused an approximately 10-fold increase in IFN-gamma production by polarized Th2 cells. These data indicate that negative regulation of TCR signaling by beta1,6GlcNAc N-glycans promotes development of Th2 over Th1 responses, enhances polarization of Th2 cells, and suggests a mechanism for the increased autoimmune disease susceptibility observed in Mgat5(-/-) mice. 相似文献
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G Z Tau S N Cowan J Weisburg N S Braunstein P B Rothman 《Journal of immunology (Baltimore, Md. : 1950)》2001,167(10):5574-5582
Previous studies have demonstrated that, as naive murine CD4(+) cells differentiate into Th1 cells, they lose expression of the second chain of IFN-gammaR (IFN-gammaR2). Hence, the IFN-gamma-producing subset of Th cells is unresponsive to IFN-gamma. Analysis of IFN-gamma-producing CD8(+) T cells demonstrates that, like Th1 cells, these cells do not express IFN-gammaR2. To define the importance of IFN-gamma signaling for the development of functional CD8(+) T cells, mice either lacking IFN-gammaR2 or overexpressing this protein were examined. While CD8(+) T cell development and function appear normal in IFN-gammaR2(-/-) mice, CD8(+) T cell function in IFN-gammaR2 transgenic is altered. IFN-gammaR2 transgenic CD8(+) T cells are unable to lyse target cells in vitro. However, these cells produce Fas ligand, perforin, and granzyme B, the effector molecules required for killing. Interestingly, TG CD8(+) T cells proliferate normally and produce cytokines, such as IFN-gamma in response to antigenic stimulation. Therefore, although IFN-gamma signaling is not required for the generation of normal cytotoxic T cells, constitutive IFN-gamma signaling can selectively impair the cytotoxic function of CD8(+) T cells. 相似文献
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Johansson-Lindbom B Ingvarsson S Borrebaeck CA 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(4):1657-1666
In the present study we demonstrate that all CD4(+) T cells in human tonsil expressing the Th2-selective receptor chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) also 1) express high levels of CXCR5, and 2) display a transitional CD45RA/RO phenotype and consistently do not produce significant amounts of cytokines when immediately analyzed ex vivo. Hence, they represent precursors of Th2 effector cells, a conclusion confirmed by their robust production of IL-4, IL-5, and IL-13, but not IFN-gamma, after in vitro activation. CD4(+) T cells, which express only intermediate levels of CXCR5, instead develop into IFN-gamma-producing cells under identical culture conditions, thus establishing a correlation between relative levels of CXCR5 expression and the acquired cytokine profile. Because CXCR5 is critically involved in follicular localization, the results suggest that these CRTH2(+) Th2 cells preferentially develop their cytokine-producing phenotype within germinal centers (GCs), whereas extrafollicular differentiation instead promotes Th1 development. In support for this proposal, we show that T cells with an intermediate expression of CXCR5 can be forced to also produce IL-4 and IL-13 if cultured with allogenic GC B cells. Finally, we demonstrate that the previously described CD57(+) GC T cells also express high levels of CXCR5 but instead of comprising a Th2 precursor, they represent anergized T cells. Taken together, these data suggest that GCs and B cells regulate CD4(+) T cell differentiation in a finely tuned fashion, either by promoting differentiation of Th2 cells, which apparently leave the lymphoid tissue before evolving a cytokine-producing phenotype, or by furnishing T cell unresponsiveness. 相似文献
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The quantity of TCR signal determines positive selection and lineage commitment of T cells 总被引:3,自引:0,他引:3
Watanabe N Arase H Onodera M Ohashi PS Saito T 《Journal of immunology (Baltimore, Md. : 1950)》2000,165(11):6252-6261
It is generally accepted that the avidity of TCR for self Ag/MHC determines the fate of immature thymocytes. However, the contribution of the quantity of TCR signal to T cell selection has not been well established, particularly in vivo. To address this issue, we analyzed DO-TCR transgenic CD3zeta-deficient (DO-Tg/zetaKO) mice in which T cells have a reduced TCR on the cell surface. In DO-Tg/zetaKO mice, very few CD4 single positive (SP) thymocytes developed, indicating that the decrease in TCR signaling resulted in a failure of positive selection of DO-Tg thymocytes. Administration of the peptide Ag to DO-Tg/zetaKO mice resulted in the generation of functional CD4 SP mature thymocytes in a dose-dependent manner, and, unexpectedly, DO-Tg CD8 SP cells emerged at lower doses of Ag. TCR signal-dependent, sequential commitment from CD8(+) SP to CD4(+) SP was also shown in a class I-restricted TCR-Tg system. These in vivo analyses demonstrate that the quantity of TCR signal directly determines positive and negative selection, and further suggest that weak signal directs positively selected T cells to CD8 lineage and stronger signal to CD4 lineage. 相似文献
9.
Papadakis KA Landers C Prehn J Kouroumalis EA Moreno ST Gutierrez-Ramos JC Hodge MR Targan SR 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(1):159-165
The chemokine receptor CCR9 is expressed on most small intestinal lamina propria and intraepithelial lymphocytes and on a small subset of peripheral blood lymphocytes. CCR9-expressing lymphocytes may play an important role in small bowel immunity and inflammation. We studied the phenotype and functional characteristics of CCR9(+) lymphocytes in blood from normal donors. A subset of CCR9(+) T cells have a phenotype of activated cells and constitutively express the costimulatory molecules CD40L and OX-40. In contrast to CCR9(-), CCR9(+)CD4(+) peripheral blood T cells proliferate to anti-CD3 or anti-CD2 stimulation and produce high levels of IFN-gamma and IL-10. IL-10-producing cells were exclusively detected within the CCR9(+) subset of CD4(+) T cells by intracellular staining and were distinct from IL-2- and IFN-gamma-producing cells. Moreover, memory CCR9(+)CD4(+) lymphocytes respond to CD2 stimulation with proliferation and IFN-gamma/IL-10 production, whereas memory CCR9(-)CD4(+) cells were unresponsive. In addition, memory CCR9(+)CD4(+) T cells support Ig production by cocultured CD19(+) B cells in the absence of prior T cell activation or addition of exogenous cytokines. Our data show that the memory subset of circulating CCR9(+)CD4(+) T cells has characteristics of mucosal T lymphocytes and contains cells with either Th1 or T-regulatory 1 cytokine profiles. Studies on the cytokine profile and Ag specificity of this cell subset could provide important insight into small intestinal immune-mediated diseases and oral tolerance in humans. 相似文献
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Hamada S Umemura M Shiono T Tanaka K Yahagi A Begum MD Oshiro K Okamoto Y Watanabe H Kawakami K Roark C Born WK O'Brien R Ikuta K Ishikawa H Nakae S Iwakura Y Ohta T Matsuzaki G 《Journal of immunology (Baltimore, Md. : 1950)》2008,181(5):3456-3463
IL-17A is originally identified as a proinflammatory cytokine that induces neutrophils. Although IL-17A production by CD4(+) Th17 T cells is well documented, it is not clear whether IL-17A is produced and participates in the innate immune response against infections. In the present report, we demonstrate that IL-17A is expressed in the liver of mice infected with Listeria monocytogenes from an early stage of infection. IL-17A is important in protective immunity at an early stage of listerial infection in the liver because IL-17A-deficient mice showed aggravation of the protective response. The major IL-17A-producing cells at the early stage were TCR gammadelta T cells expressing TCR Vgamma4 or Vgamma6. Interestingly, TCR gammadelta T cells expressing both IFN-gamma and IL-17A were hardly detected, indicating that the IL-17A-producing TCR gammadelta T cells are distinct from IFN-gamma-producing gammadelta T cells, similar to the distinction between Th17 and Th1 in CD4(+) T cells. All the results suggest that IL-17A is a newly discovered effector molecule produced by TCR gammadelta T cells, which is important in innate immunity in the liver. 相似文献
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CD4+CD25+ regulatory T cells restrain pathogenic responses during Leishmania amazonensis infection 总被引:1,自引:0,他引:1
Ji J Masterson J Sun J Soong L 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(11):7147-7153
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Reconstitution of Leishmania immunity in severe combined immunodeficient mice using Th1- and Th2-like cell lines. 总被引:16,自引:0,他引:16
B J Holaday M D Sadick Z E Wang S L Reiner F P Heinzel T G Parslow R M Locksley 《Journal of immunology (Baltimore, Md. : 1950)》1991,147(5):1653-1658
Leishmania major disseminates in genetically susceptible BALB/c mice to cause fatal disease. Progressive infection has been linked to the failure of parasite-specific Th1, IFN-gamma-producing, CD4+ T lymphocytes to expand and direct macrophage activation and control of intracellular parasitism. In contrast, Th2 CD4+ cell expansion accompanies disease progression. Immunomodulation using CD4 cell depletion at the time of infection results in control of infection and Th1 CD4+ cell expansion. A Th1-like cell line, H1A, was established from the draining lymph nodes of an anti-CD4-pretreated BALB/c mouse infected with L. major, H1A was CD4, TCR(+)-alpha/beta, and released IL-2 and IFN-gamma in response to parasite Ag. A Th2-like cell line, U1A, was established from the lymph node cells of an infected BALB/c mouse that was also CD4, TCR(+)-alpha/beta but released IL-4 and IL-5 after stimulation. Mice with severe combined immunodeficiency were reconstituted with H1A and U1A before infection with L. major. Non-reconstituted mice were unable to restrict parasite growth. Mice reconstituted with H1A healed infection, whereas mice reconstituted with U1A suffered exacerbation of disease. Analysis of spleen cells by flow cytometry confirmed the reconstitution of CD4+ cells in both instances, and stimulation with mitogen established that the lymphokine profile of the donor cells had been maintained during 6 to 8 wk of infection. Histologic analysis of the lesions confirmed migration of donated cells to sites of infection. Neutralization of IFN-gamma in H1A-reconstituted mice and IL-4 in U1A-reconstituted mice reversed the disease phenotype mediated by the two cell lines. These data demonstrate the capacity of CD4+ T cells alone to modulate both positively and negatively the course of leishmaniasis in a lymphokine-dependent manner. 相似文献
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Memory CD8+ T cells provide an early source of IFN-gamma 总被引:7,自引:0,他引:7
Kambayashi T Assarsson E Lukacher AE Ljunggren HG Jensen PE 《Journal of immunology (Baltimore, Md. : 1950)》2003,170(5):2399-2408
During the non-Ag-specific early phase of infection, IFN-gamma is believed to be primarily provided by NK and NKT cells in response to pathogen-derived inflammatory mediators. To test whether other cell types were involved in early IFN-gamma release, IFN-gamma-producing cells were visualized in spleens and lymph nodes of LPS-injected mice. In addition to NK and NKT cells, IFN-gamma was also detected in a significant fraction of CD8(+) T cells. CD8(+) T cells represented the second major population of IFN-gamma-producing cells in the spleen ( approximately 30%) and the majority of IFN-gamma(+) cells in the lymph nodes ( approximately 70%). LPS-induced IFN-gamma production by CD8(+) T cells was MHC class I independent and was restricted to CD44(high) (memory phenotype) cells. Experiments performed with C3H/HeJ (LPS-nonresponder) mice suggested that CD8(+) T cells responded to LPS indirectly through macrophage/dendritic cell-derived IFN-alpha/beta, IL-12, and IL-18. IFN-gamma was also detected in memory CD8(+) T cells from mice injected with type I IFN or with poly(I:C), a synthetic dsRNA that mimics early activation by RNA viruses. Taken together, these results suggest that in response to bacterial and viral products, memory T cells may contribute to innate immunity by providing an early non-Ag-specific source of IFN-gamma. 相似文献
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A V Gorbachev N A DiIulio R L Fairchild 《Journal of immunology (Baltimore, Md. : 1950)》2001,167(1):156-162
During sensitization with dinitrofluorobenzene for contact hypersensitivity (CHS) responses, hapten-specific CD8(+) T cells develop into IFN-gamma-producing cells, and CD4(+) T cells develop into IL-4/IL-5-producing cells. Administration of IL-12 during sensitization skews CD4(+) T cell development to IFN-gamma-producing cells, resulting in exaggerated CHS responses. In the current report we tested the role of IL-12 on CD8(+) T cell development during sensitization and elicitation of CHS to dinitrofluorobenzene. Administration of IL-12 during hapten sensitization induced the expression of IL-12Rbeta2 on both CD4(+) and CD8(+) T cells, augmented IFN-gamma production by these T cell populations, and increased the magnitude and duration of the CHS response to hapten challenge. CHS responses were virtually identical in wild-type and IL-12 p40(-/-) mice. Since engagement of CD40 on APC may stimulate IL-12 production, we also tested the role of CD40-CD154 interactions on the development of IFN-gamma-producing CD4(+) and CD8(+) T cells following hapten sensitization. Development of IFN-gamma-producing CD4(+) T cells during hapten sensitization was absent in wild-type mice treated with anti-CD154 mAb or in CD154(-/-) mice. In contrast, the absence of CD40-CD154 signaling had little or no impact on the development of IFN-gamma-producing CD8(+) T cells. These results demonstrate that the development of hapten-specific Th1 effector CD4(+) T cells in CHS requires both CD40-CD154 interactions and IL-12, whereas the development of IFN-gamma-producing effector CD8(+) T cells can occur independently of these pathways. 相似文献
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Vgamma4(+) T cells promote autoimmune CD8(+) cytolytic T-lymphocyte activation in coxsackievirus B3-induced myocarditis in mice: role for CD4(+) Th1 cells
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T cells expressing the Vgamma4 T-cell receptor (TCR) promote myocarditis in coxsackievirus B3 (CVB3)-infected BALB/c mice. CD1, a major histocompatibility complex (MHC) class I-like molecule, is required for activation of Vgamma4(+) cells. Once activated, Vgamma4(+) cells initiate myocarditis through gamma interferon (IFN-gamma)-mediated induction of CD4(+) T helper type 1 (Th1) cells in the infected animal. These CD4(+) Th1 cells are required for activation of an autoimmune CD8(+) alphabeta TCR(+) effector, which is the predominant pathogenic agent in this model of CVB3-induced myocarditis. Activated Vgamma4(+) cells can adoptively transfer myocarditis into BALB/c mice infected with a nonmyocarditic variant of CVB3 (H310A1) but cannot transfer myocarditis into either uninfected or CD1(-/-) recipients, demonstrating the need for both infection and CD1 expression for Vgamma4(+) cell function. In contrast, CD8(+) alphabeta TCR(+) cells transfer myocarditis into either infected CD1(-/-) or uninfected recipients, showing that once activated, the CD8(+) alphabeta TCR(+) effectors function independently of both virus and CD1. Vgamma4(+) cells given to mice lacking CD4(+) T cells minimally activate the CD8(+) alphabeta TCR(+) cells. These studies show that Vgamma4(+) cells determine CVB3 pathogenicity by their ability to influence both the CD4(+) and CD8(+) adaptive immune response. Vgamma4(+) cells enhance CD4(+) Th1 (IFN-gamma(+)) cell activation through IFN-gamma- and CD1-dependent mechanisms. CD4(+) Th1 cells promote activation of the autoimmune CD8(+) alphabeta TCR(+) effectors. 相似文献
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Skapenko A Lipsky PE Kraetsch HG Kalden JR Schulze-Koops H 《Journal of immunology (Baltimore, Md. : 1950)》2001,166(7):4283-4292
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Phenotypic and functional characterization of CD4 T cells expressing killer Ig-like receptors 总被引:6,自引:0,他引:6
van Bergen J Thompson A van der Slik A Ottenhoff TH Gussekloo J Koning F 《Journal of immunology (Baltimore, Md. : 1950)》2004,173(11):6719-6726
Killer Ig-like receptors (KIR) are commonly found on human NK cells, gammadelta T cells, and CD8 T cells. Although KIR(+) CD4 T cells are found in certain patients, their prevalence in healthy donors is controversial. We now provide definitive proof that such cells are present in most individuals, and report on their frequency, surface phenotype, cytokine profile, and Ag specificity. The number of KIR(+) CD4 T cells detected in peripheral blood increased with age. In contrast with regular KIR(-) CD4 T cells, the majority of KIR(+) CD4 T cells lacked surface expression of CD27, CD28, CCR4, and CCR7, but did express CD57 and 2B4. In addition, KIR were detected on approximately one-tenth of CD28(-) and CD57(+) memory CD4 T cells. In line with the absence of the Th2 marker CCR4, the KIR(+) CD4 cells produced mainly IFN-gamma and little IL-4, IL-10, or IL-17 upon TCR triggering. Furthermore, the KIR(+) population contained cells that responded to recall Ags in an HLA class II-restricted fashion. Together, our data indicate that KIR-expressing CD4 T cells are predominantly HLA class II-restricted effector memory Th1 cells, and that a significant, previously unrecognized fraction of effector memory Th1 cells expresses KIR. 相似文献
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Haring JS Badovinac VP Olson MR Varga SM Harty JT 《Journal of immunology (Baltimore, Md. : 1950)》2005,175(5):3117-3122
The precise mechanisms that govern the commitment of CD4 T cells to become Th1 or Th2 cells in vivo are incompletely understood. Recent experiments demonstrate colocalization of the IFN-gammaR chains with the TCR during activation of naive CD4 T cells, suggesting that association of these molecules may be involved in determining lineage commitment. To test the role of IFN-gamma and its receptor in the generation of Th1 Ag-specific CD4 T cells, we analyzed mice after infection with Listeria monocytogenes or lymphocytic choriomeningitis virus. In the absence of IFN-gamma, Ag-specific CD4 T cells were generated in response to both these infections. In addition, IFN-gamma-producing (Th1) Ag-specific CD4 T cells were generated in mice lacking the ligand-binding chain of the IFN-gammaR (IFN-gammaR1-/-) or the signaling chain (IFN-gammaR2-/-). There was no increase in the number of IL-4-producing Ag-specific CD4 T cells, nor was there a decrease in the expression of T-bet in the absence of functional IFN-gamma signaling, indicating that the cells were committed Th1 cells. Thus, both chains of the IFN-gammaR are dispensable for the generation of Th1 Ag-specific CD4 T cells after infection in vivo. 相似文献
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Geiger TL Leitenberg D Flavell RA 《Journal of immunology (Baltimore, Md. : 1950)》1999,162(10):5931-5939
The TCR complex signals through a set of 10 intracytoplasmic motifs, termed immunoreceptor tyrosine-based activation motifs (ITAMs), contained within the gamma-, delta-, epsilon-, and zeta-chains. The need for this number of ITAMs is uncertain. Limited and contradictory studies have examined the ability of subsets of the TCR's ITAMs to signal into postthymic primary T lymphocytes. To study signaling by a restricted set of ITAMs, we expressed in transgenic mice a chimeric construct containing the IAs class II MHC extracellular and transmembrane domains linked to the cytoplasmic domain of the TCR zeta-chain. Tyrosine phosphorylation and receptor cocapping studies indicate that this chimeric receptor signals T cells independently of the remainder of the TCR. We show that CD4+ and CD8+ primary T cells, as well as naive and memory T cells, are fully responsive to stimulation through the IAs-zeta receptor. Further, IAs-zeta stimulation can induce primary T cell differentiation into CTL, Th1, and Th2 type cells. These results show that the zeta-chain ITAMs, in the absence of the gamma, delta, and epsilon ITAMs, are sufficient for the activation and functional maturation of primary T lymphocytes. It also supports the isolated use of the zeta-chain ITAMs in the development of surrogate TCRs for therapeutic purposes. 相似文献