Generation and maintenance of antigen-specific effector and memory T cells are central events in immune responses against infections. We show that TNF receptor-associated factor 2 (TRAF2) maintains a survival signaling axis in effector and memory CD8 T cells required for immune responses against infections. This signaling axis involves activation of Tpl2 and its downstream kinase ERK by NF-κB-inducing kinase (NIK) and degradation of the proapoptotic factor Bim. NIK mediates Tpl2 activation by stimulating the phosphorylation and degradation of the Tpl2 inhibitor p105. Interestingly, while NIK is required for Tpl2-ERK signaling under normal conditions, uncontrolled NIK activation due to loss of its negative regulator, TRAF2, causes constitutive degradation of p105 and Tpl2, leading to severe defects in ERK activation and effector/memory CD8 T cell survival. Thus, TRAF2 controls a previously unappreciated signaling axis mediating effector/memory CD8 T cell survival and protective immunity.

抗原特异性效应细胞和记忆 T 细胞的产生和维持是针对感染的免疫反应的核心事件。我们发现，TNF 受体相关因子 2 (TRAF2) 在效应细胞和记忆 CD8 T 细胞中维持针对感染的免疫反应所需的生存信号轴。该信号轴涉及 NF-κB 诱导激酶 (NIK) 激活 Tpl2 及其下游激酶 ERK 以及促凋亡因子 Bim 的降解。 NIK 通过刺激 Tpl2 抑制剂 p105 的磷酸化和降解来介导 Tpl2 激活。有趣的是，虽然正常条件下 Tpl2-ERK 信号传导需要 NIK，但由于负调节因子 TRAF2 的丢失，NIK 激活不受控制，会导致 p105 和 Tpl2 的组成性降解，导致 ERK 激活和效应/记忆 CD8 T 细胞的严重缺陷生存。因此，TRAF2 控制着一个以前未被认识到的信号轴，介导效应/记忆 CD8 T 细胞存活和保护性免疫。