IKK signalling is essential for survival of thymocytes by repressing RIPK1 induced cell death rather than its canonical function of activating NF-κB. The role of IKK signalling in activated T cells is unclear. To investigate this, we analysed activation of IKK2 deficient T cells. While TCR triggering was normal, proliferation and expansion was profoundly impaired. This was not due to defective cell cycle progression, rather dividing T cells became sensitised to TNF induced cell death, since inhibition of RIPK1 kinase activity rescued cell survival. Gene expression analysis of activated IKK2 deficient T cells revealed defective expression of Tnfaip3, that encodes A20, a negative regulator of NF-κB. To test whether A20 expression was required to protect IKK2 deficient T cells from cell death, we generated mice with T cells lacking both A20 and IKK2. Doing this resulted in near complete loss of peripheral T cells, in contrast to mice lacking one or other gene. Strikingly, this phenotype was completely reversed by inactivation of RIPK1 kinase activity in vivo. Together, our data show that IKK signalling in activated T cells protects against RIPK1 dependent death, both by direct phosphorylation of RIPK1 and through NF-κB mediated induction of A20, that we identify for the first time as a key modulator of RIPK1 activity in T cells.

IKK 信号转导通过抑制 RIPK1 诱导的细胞死亡而不是其激活 NF-κB 的典型功能，对胸腺细胞的生存至关重要。 IKK 信号传导在活化 T 细胞中的作用尚不清楚。为了研究这一点，我们分析了 IKK2 缺陷 T 细胞的激活。虽然 TCR 触发正常，但增殖和扩张受到严重损害。这并不是由于细胞周期进程有缺陷，而是分裂的 T 细胞对 TNF 诱导的细胞死亡变得敏感，因为抑制 RIPK1 激酶活性可以挽救细胞存活。对活化的 IKK2 缺陷型 T 细胞进行基因表达分析，发现Tnfaip3表达有缺陷，Tnfaip3 编码 A20（NF-κB 的负调节因子）。为了测试是否需要表达 A20 来保护 IKK2 缺陷的 T 细胞免于细胞死亡，我们培育了 T 细胞同时缺乏 A20 和 IKK2 的小鼠。与缺乏一种或另一种基因的小鼠相比，这样做会导致外周 T 细胞几乎完全丧失。引人注目的是，这种表型通过体内 RIPK1 激酶活性的失活而完全逆转。总之，我们的数据表明，激活的 T 细胞中的 IKK 信号传导可通过 RIPK1 的直接磷酸化和 NF-κB 介导的 A20 诱导来防止 RIPK1 依赖性死亡，我们首次将 A20 确定为 T 细胞中 RIPK1 活性的关键调节剂。细胞。