T-bet Inhibits the In Vivo Differentiation of Parasite-Specific CD4+ Th17 Cells in a T Cell-Intrinsic Manner
T-bet Inhibits the In Vivo Differentiation of Parasite-Specific CD4+ Th17 Cells in a T Cell-Intrinsic Manner
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DOI：
10.4049/jimmunol.0803821
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发表时间：
2009-05-15
影响因子：
4.4
通讯作者：
Smeltz, Ronald B.
中科院分区：
文献类型：
--
作者：
Guo, Siqi;Cobb, Dustin;Smeltz, Ronald B.
CD 4（+）Th 17细胞作为Th 1/Th 2模式中的一个新的T细胞亚群出现，并且努力转向了解调节其体内发育的因素。为了分析转录因子T-bet在调节Th 17细胞中的作用，我们使用了克氏锥虫感染的小鼠模型，克氏锥虫是一种引起人类恰加斯病的原生动物寄生虫。感染Tbx 21（-/-）小鼠导致产生IFN-γ的Ag特异性CD 4（+）T细胞的正常、未受损的发育。然而，强有力的Th 17反应与Th 1反应同时出现。尽管IFN-γ产生显著，但Th 17应答的生理效应占主导地位，因为Gr-1（+）Ly 6 G（+）中性粒细胞急剧增加。将T细胞从感染的Tbr 21（-/-）小鼠连续转移到Rag-2（-/-）小鼠（Tbx 21（+/+））中显示，CD 4（+）T细胞保持其产生IL-17的表型，包括能够产生IFN-γ和IL-17的那些细胞。此外，与IL-2对Th 17发育的影响相反，IL-2对致敏T细胞的IL-17产生没有影响。重要的是，将T细胞从未处理的Tbx 21（-/-）小鼠过继转移到感染的Rag-2-/-小鼠中重现了T细胞的分化。在感染的Tbx 21（-/-）小鼠中观察到cruzi特异性Th 17细胞。相反，将野生型T细胞转移到感染的Tbx 21（-/-）小鼠中并没有显示出Th 17发育的增加。这些结果表明，T-bet调节T.以T细胞内在方式体内培养克鲁兹特异性Th 17细胞。这些数据为T-bet在调节寄生虫特异性Th 17应答中的作用提供了重要的见解。免疫学杂志，2009，182：6179-6186.
CD4(+) Th17 cells have emerged as a new T cell subset in the Th1/Th2 paradigm, and efforts have shifted toward understanding the factors that regulate their development in vivo. To analyze the role of the transcription factor T-bet in regulation of Th17 cells, we used a murine model of Trypanosoma cruzi infection, a protozoan parasite that causes Chagas disease in humans. Infection of Tbx21(-/-) mice led to normal, unimpaired development of Ag-specific CD4(+) T cells producing IFN-gamma. However, a robust Th17 response developed concomitant with Th1 responses. Despite significant IFN-gamma production, the physiological effects of Th17 responses prevailed as there was a sharp increase in Gr-1(+)Ly6G(+) neutrophils. Adoptive transfer of T cells from infected Tbr21(-/-) mice into Rag-2(-/-) mice (Tbx21(+/+)) revealed that CD4(+) T cells maintained their IL-17-producing phenotype, including those cells capable of producing both IFN-gamma and IL-17. Furthermore, and in contrast to the effects of IL-2 on Th17 development, IL-2 had no effect on IL-17 production by primed T cells. Importantly, adoptive transfer of T cells from naive Tbx21(-/-) mice into infected Rag-2-/- mice recapitulated the differentiation of T. cruzi-specific Th17 cells observed in infected Tbx21(-/-) mice. Conversely, transfer of wild-type T cells into infected Tbx21(-/-) mice did not reveal an increase in Th17 development. These results demonstrate that T-bet regulates the differentiation of T. cruzi-specific Th17 cells in vivo in a T cell-intrinsic manner. These data provide important insight into the role of T-bet in regulation of parasite-specific Th17 responses. The Journal of Immunology, 2009, 182: 6179-6186.