IKK controls naive T cell survival by repressing RIPK1 dependent apoptosis and activation of NF-κB

The Inhibitor of Kappa B Kinase (IKK) complex is a critical regulator of NF-κB activation. In addition, IKK has recently been shown to repress RIPK1 dependent extrinsic cell death pathways by directly phosphorylating RIPK1. Our previous work shows that normal thymopoiesis relies on IKK exclusively for repression of TNF triggered cell death pathways, and that NF-κB activation by IKK is redundant for development. The role of these pathways in mature naive T cells has not previously been reported. Here, we show that, like thymocytes, naive peripheral T cells require continued IKK1/2 expression for survival. In contrast, however, cell loss is only partially prevented by blocking extrinsic cell death pathways by either deleting Casp8 or inhibiting RIPK1 kinase activity. Inducible deletion of Rela in mature CD4+ T cells also results in a significant loss of naive CD4+ T cells and loss of IL7R expression, revealing an additional reliance upon NF-κB for long term survival of mature T cells. Together, these data show that IKK dependent survival of naive T cells depends upon both repression of extrinsic cell death pathways and activation of NF-κB survival programme. One sentence summary IKK regulates naive T cell survival