IKK promotes naive T cell survival by repressing RIPK1-dependent apoptosis and activating NF-κB

The inhibitor of ?B kinase (IKK) complex regulates the activation of the nuclear factor ?B (NF-?B) family of transcription factors. In addition, IKK represses extrinsic cell death pathways dependent on receptor-interacting serine/threonine-protein kinase 1 (RIPK1) by directly phosphorylating this kinase. Here, we showed that peripheral naive T cells in mice required the continued expression of IKK1 and IKK2 for their survival; however, the loss of these cells was only partially prevented when extrinsic cell death pathways were blocked by either deleting Casp8 (which encodes the apoptosis-inducing caspase 8) or inhibiting the kinase activity of RIPK1. Inducible deletion of Rela (which encodes the NF-?B p65 subunit) in mature CD4(+) T cells also resulted in loss of naive CD4(+) T cells and in reduced abundance of the interleukin-7 receptor (IL-7R) encoded by the NF-?B target Il7r, revealing an additional reliance upon NF-?B for the long-term survival of mature T cells. Together, these data indicate that the IKK-dependent survival of naive CD4(+) T cells depends on both repression of extrinsic cell death pathways and activation of an NF-?B-dependent survival program.