Marie Julien C, Liggitt Denny, Rudensky Alexander Y
Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Immunity. 2006 Sep;25(3):441-54. doi: 10.1016/j.immuni.2006.07.012.
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-betaRII) deficiency activated cytolytic and T helper 1 (Th1) differentiation program in a cell-intrinsic T cell receptor (TCR)-specific fashion. Furthermore, TGF-betaRII 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.
转化生长因子-β（TGF-β）参与多种细胞类型的分化和增殖调控。然而，由于其多效性作用，TGF-β在免疫稳态调控中的作用尚未完全明确。在此我们报告，T细胞中TGF-β信号的完全缺失会导致侵袭性早发性多器官自身免疫相关病变，死亡率达100%。外周CD4⁺和CD8⁺T细胞中TGF-β受体II（TGF-βRII）缺陷以细胞内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，TGF-βRII缺陷阻碍了经典的CD1d限制性自然杀伤T细胞（NKT细胞）的发育。相反，它促进了一种高致病性T细胞亚群的产生，该亚群表现出自然杀伤细胞的多种特征，并显著增加了FasL、穿孔素、颗粒酶和干扰素-γ的量。因此，外周T细胞中的TGF-β信号对于抑制TCR激活依赖性的Th1、细胞毒性和自然杀伤细胞样分化程序至关重要，若不加控制，会导致迅速进展的致命自身免疫。
