Mucosal Immunology Section, NIDCR, NIH, Bethesda, MD 20892, USA.
Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
Immunity. 2018 Apr 17;48(4):745-759.e6. doi: 10.1016/j.immuni.2018.03.025.
It is unclear how quiescence is enforced in naive T cells, but activation by foreign antigens and self-antigens is allowed, despite the presence of inhibitory signals. We showed that active transforming growth factor β (TGF-β) signaling was present in naive T cells, and T cell receptor (TCR) engagement reduced TGF-β signaling during T cell activation by downregulating TGF-β type 1 receptor (TβRI) through activation of caspase recruitment domain-containing protein 11 (CARD11) and nuclear factor κB (NF-κB). TGF-β prevented TCR-mediated TβRI downregulation, but this was abrogated by interleukin-6 (IL-6). Mitigation of TCR-mediated TβRI downregulation through overexpression of TβRI in naive and activated T cells rendered T cells less responsive and suppressed autoimmunity. Naive T cells in autoimmune patients exhibited reduced TβRI expression and increased TCR-driven proliferation compared to healthy subjects. Thus, TCR-mediated regulation of TβRI-TGF-β signaling acts as a crucial criterion to determine T cell quiescence and activation.
目前尚不清楚幼稚 T 细胞中如何强制休眠，但尽管存在抑制信号，仍允许幼稚 T 细胞被外来抗原和自身抗原激活。我们发现，在幼稚 T 细胞中存在活跃的转化生长因子β（TGF-β）信号，T 细胞受体（TCR）的结合通过激活半胱天冬酶募集结构域蛋白 11（CARD11）和核因子 κB（NF-κB），下调 TGF-β 型 1 受体（TβRI），从而在 T 细胞激活过程中降低 TGF-β 信号。TGF-β 可防止 TCR 介导的 TβRI 下调，但这一过程被白细胞介素 6（IL-6）所阻断。在幼稚和激活的 T 细胞中过表达 TβRI 可减轻 TCR 介导的 TβRI 下调，从而降低 T 细胞的反应性并抑制自身免疫。与健康受试者相比，自身免疫患者的幼稚 T 细胞表现出 TβRI 表达减少和 TCR 驱动的增殖增加。因此，TCR 介导的 TβRI-TGF-β 信号调节可作为决定 T 细胞休眠和激活的关键标准。
