Abstract
SummaryNF-κB (nuclear factor κB) signaling is considered critical for single positive (SP) thymocyte development because loss of upstream activators of NF-κB, such as the IKK complex, arrests their development. We found that the compound ablation of RelA, cRel, and p50, required for canonical NF-κB transcription, had no impact upon thymocyte development. While IKK-deficient thymocytes were acutely sensitive to tumor necrosis factor (TNF)-induced cell death, Rel-deficient cells remained resistant, calling into question the importance of NF-κB as the IKK target required for thymocyte survival. Instead, we found that IKK controlled thymocyte survival by repressing cell-death-inducing activity of the serine/threonine kinase RIPK1. We observed that RIPK1 expression was induced during development of SP thymocytes and that IKK was required to prevent RIPK1-kinase-dependent death of SPs in vivo. Finally, we showed that IKK was required to protect Rel-deficient thymocytes from RIPK1-dependent cell death, underscoring the NF-κB-independent function of IKK during thymic development.
Highlights
T lymphocytes develop in the thymus from pluripotent bonemarrow-derived progenitors through an ordered sequence of developmental events
Development and Survival of single positive (SP) Thymocytes Does Not Depend on nuclear factor kB (NF-kB) To directly ask whether NF-kB signaling is required for SP thymocyte development, we generated mice with compound deficiencies of the three Rel family members required for canonical NF-kB signaling: RelA, cRel, and p50
To confirm that canonical NF-kB signaling was absent in RelADT RelÀ/À Nfkb1À/À tripledeficient thymocytes, we first tested their capacity to proliferate in response to CD3+CD28 stimulation
Summary
T lymphocytes develop in the thymus from pluripotent bonemarrow-derived progenitors through an ordered sequence of developmental events. There has been considerable interest in identifying those signaling pathways and transcriptional networks responsible for controlling different aspects of thymic development. NF-kB signaling is mediated by heterodimers or homodimers of p50, RelA, and cRel family members that are sequestered in the cytoplasm by inhibitory proteins, the inhibitors of kappa B (IkB) family, and related protein p105. Release of canonical NF-kB dimers is controlled by the inhibitor of kappa B kinase (IKK) complex, a trimeric complex of two kinases, IKK1 (IKKa) and IKK2 (IKKb), and a third regulatory component, NEMO (IKKg). IKK, activated by the upstream TAK1-TAB1 (transforming growth factor [TGF]-b-activated kinase 1 and TAK1-binding protein 1) kinase complex, phosphorylates IkB, resulting in its degradation by the proteosome and permitting NF-kB dimers to enter the nucleus. It is notable that TCR activation of the IKK complex is mediated via a signalosome complex comprising Card, Bcl, and Malt proteins (the CBM complex) that is not required for thymocyte development (SchmidtSupprian et al, 2004)
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