Journal
IMMUNITY
Volume 50, Issue 2, Pages 348-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2019.01.004
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Funding
- Belgian (Interuniversity Attraction Poles) [IAP 7/32, EOS 30826052 MODEL-IDI]
- Flemish (Research Foundation Flanders) [FWO G.0875.11, G.0973.11, G.0A45.12N, G.0787.13N, G.0C31.14N, G.0C37.14N, G.0E04.16N, G.0C76.18N, G.0B71.18N]
- Methusalem grant [BOF16/MET_V/007]
- Ghent University (MRP, GROUP-ID consortium)
- Foundation against Cancer [2012-188, FAF-F/2016/865]
- VIB
- Medical Research Council UK [MC_PC_13055, MR/P011225/1]
- MRC [MR/P011225/1, MC_PC_13055] Funding Source: UKRI
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NF-kappa B(nuclear factor kappa B) signaling is considered critical for single positive (SP) thymocyte development because loss of upstream activators of NF-kappa B, such as the IKK complex, arrests their development. We found that the compound ablation of RelA, cRel, and p50, required for canonical NF-kappa B 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-kappa B 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-kappa B-independent function of IKK during thymic development.
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