Generation of a diverse and self-tolerant T-cell repertoire requires appropriate interpretation of T-cell antigen receptor (TCR) signals by CD4+CD8+ double-positive thymocytes. Thymocyte cell fate is dictated by the nature of TCR–major-histocompatibility-complex (MHC)–peptide interactions, with signals of higher strength leading to death (negative selection) and signals of intermediate strength leading to differentiation (positive selection)1. Molecules that regulate T-cell development by modulating TCR signal strength have been described but components that specifically define the boundaries between positive and negative selection remain unknown. Here we show in mice that repression of TCR-induced death pathways is critical for proper interpretation of positive selecting signals in vivo, and identify schnurri-2 (Shn2; also known as Hivep2) as a crucial death dampener. Our results indicate that Shn2−/− double-positive thymocytes inappropriately undergo negative selection in response to positive selecting signals, thus leading to disrupted T-cell development. Shn2−/− double-positive thymocytes are more sensitive to TCR-induced death in vitro and die in response to positive selection interactions in vivo. However, Shn2-deficient thymocytes can be positively selected when TCR-induced death is genetically ablated. Shn2 levels increase after TCR stimulation, indicating that integration of multiple TCR–MHC–peptide interactions may fine-tune the death threshold. Mechanistically, Shn2 functions downstream of TCR proximal signalling compenents to dampen Bax activation and the mitochondrial death pathway. Our findings uncover a critical regulator of T-cell development that controls the balance between death and differentiation.
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The authors thank R. Davis for providing Bim phospho-Thr-112 specific antibody; R. Germain for providing DAP3 and P139 cell lines; M. Winslow and E. Gallo for critical reading of the manuscript and valuable comments. T.L.S. is a Fellow of the Leukemia and Lymphoma Society and V.L. was a Fellow of the Irvington Institute. Supported by the National Institutes of Health grant AI29673 (L.H.G.) and K99AR055668 (D.C.J.).
L.H.G. is a member of the Board of Directors of the Bristol-Myers Squibb Pharmaceutical Company.
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Staton, T., Lazarevic, V., Jones, D. et al. Dampening of death pathways by schnurri-2 is essential for T-cell development. Nature 472, 105–109 (2011). https://doi.org/10.1038/nature09848
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