Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-β receptor
Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-β receptor
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DOI：
10.1016/j.immuni.2006.07.012
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发表时间：
2006-09-01
期刊：
影响因子：
32.4
通讯作者：
Rudensky, Alexander Y.
中科院分区：
文献类型：
--
作者：
Marie, Julien C.;Liggitt, Denny;Rudensky, Alexander Y.
转化生长因子-β(转化生长因子-β)参与多种细胞的分化和增殖调控。然而，由于转化生长因子-β的多效性，其在免疫稳态控制中的作用还不完全清楚。在这里，我们报告完全去除T细胞中的转化生长因子-β信号会导致侵袭性的早发性、多器官、自身免疫相关的损害，死亡率为100%。缺乏转化生长因子-β受体II(TGF-βRII)的外周血中的CD4(+)和CD8(+)T细胞以细胞固有T细胞受体(TCR)特异性方式激活细胞溶解和辅助性T细胞1(Th1)分化程序。此外，转化生长因子-βRII缺乏阻碍了CD1d限制性NKT细胞的发育。相反，它促进了高致病性T细胞亚群的产生，表现出NK细胞的多种特征，并大幅增加了FasL、穿孔素、颗粒酶和干扰素-γ的数量。因此，外周T细胞中的转化生长因子-β信号在抑制TCR激活依赖的Th1、细胞毒和NK细胞样分化程序中起着至关重要的作用，如果不加以控制，这些分化程序会导致迅速发展的致命自身免疫。
Transforming growth factor-beta (TGF-beta) has been implicated in the control of differentiation and proliferation of multiple cell types. However, a role for TGF-beta in the control of immune homeostasis is not fully understood because of its pleiotropic action. Here we report that complete ablation of the TGF-beta signaling in T cells engendered aggressive early-onset, multiorgan, autoimmune-associated lesions with 100% mortality. Peripheral CD4(+) and CD8(+) T cells with TGF-beta-receptor II (TGF-beta RII) deficiency activated cytolytic and T helper 1 (Th1) differentiation program in a cell-intrinsic T cell receptor (TCR)-specific fashion. Furthermore, TGF-beta RII deficiency blocked the development of canonical CD1d-restricted NKT cells. Instead, it facilitated generation of a highly pathogenic T cell subset exhibiting multiple hallmarks of NK cells and sharply elevated amounts of FasL, perforin, granzymes, and interferon-gamma. Thus, TGF-beta signaling in peripheral T cells is crucial in restraining TCR activation-dependent Th1, cytotoxic, and NK cell-like differentiation program which, when left unchecked, leads to rapidly progressing fatal autoimmunity.