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

• Published in: Science signaling 2023-06, Vol.16 (791), p.eabo4094-eabo4094
• Main Authors: Carty, Fiona, Layzell, Scott, Barbarulo, Alessandro, Islam, Farjana, Webb, Louise V, Seddon, Benedict
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - genetics; Cell death; Cell survival; Cell Survival - genetics; Differentiation (biology); I-kappa B Kinase - genetics; I-kappa B Kinase - metabolism; Kinases; Lymphocytes; Lymphocytes T; Mice; Mortality; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB protein; Survival; T-Lymphocytes - metabolism
• ISSN: 1945-0877; 1937-9145
• DOI: 10.1126/scisignal.abo4094

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 (which encodes the apoptosis-inducing caspase 8) or inhibiting the kinase activity of RIPK1. Inducible deletion of (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 , 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.