Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
Institute for Research in Molecular Medicine, Main Campus, Universiti Sains Malaysia, 11800 Pulau Pinang, Malaysia.
Sci Signal. 2019 Feb 5;12(567):eaav4373. doi: 10.1126/scisignal.aav4373.
T cell activation is initiated by signaling molecules downstream of the T cell receptor (TCR) that are organized by adaptor proteins. CIN85 (Cbl-interacting protein of 85 kDa) is one such adaptor protein. Here, we showed that CIN85 limited T cell responses to TCR stimulation. Compared to activated wild-type (WT) T cells, those that lacked CIN85 produced more IL-2 and exhibited greater proliferation. After stimulation of WT T cells with their cognate antigen, CIN85 was recruited to the TCR signaling complex. Early TCR signaling events, such as phosphorylation of ζ-chain-associated protein kinase 70 (Zap70), Src homology 2 (SH2) domain-containing leukocyte protein of 76 kDa (SLP76), and extracellular signal-regulated kinase (Erk), were enhanced in CIN85-deficient T cells. The inhibitory function of CIN85 required the SH3 and PR regions of the adaptor, which associated with the phosphatase suppressor of TCR signaling-2 (Sts-2) after TCR stimulation. Together, our data suggest that CIN85 is recruited to the TCR signaling complex and mediates inhibition of T cell activation through its association with Sts-2.
T 细胞的激活是由 T 细胞受体（TCR）下游的信号分子启动的，这些信号分子由衔接蛋白组织。CIN85（85kDa 的 Cbl 相互作用蛋白）就是这样一种衔接蛋白。在这里，我们表明 CIN85 限制了 T 细胞对 TCR 刺激的反应。与激活的野生型（WT）T 细胞相比，缺乏 CIN85 的细胞产生更多的 IL-2 并表现出更强的增殖。在 WT T 细胞被其同源抗原刺激后，CIN85 被招募到 TCR 信号复合物中。早期的 TCR 信号事件，如 ζ 链相关蛋白激酶 70（Zap70）、Src 同源 2（SH2）结构域含有白细胞蛋白 76kDa（SLP76）和细胞外信号调节激酶（Erk）的磷酸化，在 CIN85 缺陷型 T 细胞中增强。衔接蛋白的 SH3 和 PR 区域介导 CIN85 的抑制功能，该功能在 TCR 刺激后与 TCR 信号抑制因子-2（Sts-2）相关联。总之，我们的数据表明 CIN85 被招募到 TCR 信号复合物中，并通过与 Sts-2 的关联来介导 T 细胞激活的抑制。
