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

The inhibitor of κB kinase (IKK) complex regulates the activation of the nuclear factor κB (NF-κB) 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 naïve 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-κB p65 subunit) in mature CD4+ T cells also resulted in loss of naïve CD4+ T cells and in reduced abundance of the interleukin-7 receptor (IL-7R) encoded by the NF-κB target Il7r, revealing an additional reliance upon NF-κB for the long-term survival of mature T cells. Together, these data indicate that the IKK-dependent survival of naïve CD4+ T cells depends on both repression of extrinsic cell death pathways and activation of an NF-κB–dependent survival program. Description Naïve mouse T cell homeostasis requires both IKK-mediated inhibition of death and activation of survival pathways. Editor’s summary Mouse thymocyte survival depends on the suppression of cell death by the inhibitor of κB (IKK) complex, which phosphorylates and inactivates the cell death–promoting kinase RIPK1. Using lineage-specific, conditional knockout mice, Carty et al. investigated the role of IKK in the survival of mature naïve T cells after they leave the thymus. In addition to inhibiting RIPK1-dependent cell death, IKK also activated NF-κB–dependent, pro-survival signaling, which depended on the cytokine receptor IL-7R. Together, these data indicate how cell death and NF-κB signaling pathways are modulated during cellular differentiation.–John F. Foley

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