Dampening of death pathways by Schnurri 2 is essential for T cell development

Generation of a diverse and self-tolerant T cell repertoire requires appropriate interpretation of T cell receptor (TCR) signals by CD4(+)CD8(+) double positive (DP) thymocytes. Thymocyte cell fate is dictated by the nature of TCR: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 that repression of TCR-induced death pathways is critical for proper interpretation of positive selecting signals in vivo, and identify Schnurri2 (Shn2) as a crucial death dampener. Our results indicate that Shn2(−/−) DP thymocytes inappropriately undergo negative selection in response to positive selecting signals, thus leading to disrupted T cell development. Shn2(−/−) DP 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 suggesting that integration of multiple TCR:MHC-peptide interactions may fine tune the death threshold. Mechanistically, Shn2 functions downstream of TCR proximal signaling 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.