Graduate Program in Immunology, Iowa City, IA, 52242, USA.
Biomedical Engineering, Iowa City, IA, 52242, USA.
Sci Rep. 2017 May 18;7(1):2081. doi: 10.1038/s41598-017-02280-4.
The adaptor protein TNF receptor associated factor (TRAF) 3 is required for effective TCR signaling and normal T cell effector functions, and associates with the CD3/CD28 complex upon activation. To determine how TRAF3 promotes proximal TCR signaling, we studied TRAF3-deficient mouse and human T cells, which showed a marked reduction in activating phosphorylation of the TCR-associated kinase Lck. The impact of TRAF3 on this very early signaling event led to the hypothesis that TRAF3 restrains one or both of two known inhibitors of Lck, C-terminal Src kinase (Csk) and protein tyrosine phosphatase N22 (PTPN22). TRAF3 associated with Csk, promoting the dissociation of Csk from the plasma membrane. TRAF3 also associated with and regulated the TCR/CD28 induced localization of PTPN22. Loss of TRAF3 resulted in increased amounts of both Csk and PTPN22 in T cell membrane fractions and decreased association of PTPN22 with Csk. These findings identify a new role for T cell TRAF3 in promoting T cell activation, by regulating localization and functions of early TCR signaling inhibitors.
衔接蛋白 TNF 受体相关因子（TRAF）3 对于有效的 TCR 信号转导和正常 T 细胞效应功能是必需的，并且在激活时与 CD3/CD28 复合物相关联。为了确定 TRAF3 如何促进近端 TCR 信号转导，我们研究了 TRAF3 缺陷型小鼠和人 T 细胞，它们显示 TCR 相关激酶 Lck 的激活磷酸化明显减少。TRAF3 对这个非常早期的信号事件的影响导致了这样的假设，即 TRAF3 抑制了两种已知的 Lck 抑制剂之一或两者，即 C 末端Src 激酶（Csk）和蛋白酪氨酸磷酸酶 N22（PTPN22）。TRAF3 与 Csk 结合，促进 Csk 从质膜解离。TRAF3 还与 TCR/CD28 诱导的 PTPN22 定位相关，并调节其活性。TRAF3 的缺失导致 T 细胞质膜部分中 Csk 和 PTPN22 的含量增加，而 PTPN22 与 Csk 的结合减少。这些发现确定了 T 细胞 TRAF3 在促进 T 细胞激活中的一个新作用，通过调节早期 TCR 信号抑制剂的定位和功能。
