A discrete T cell receptor repertoire is censored at wave 1 of thymic selection (#19)
Self-reactive thymocytes that bind strongly to a self-antigen in the thymic cortex are prevented from becoming naïve conventional T cells (T-conv) by a number of mechanisms. Many self-reactive thymocytes are deleted by apoptosis, whereas agonist selection in the thymic cortex diverts other self-reactive thymocytes into the intestinal CD8αα+ intraepithelial lymphocyte (IEL) lineage. Two thymocyte-intrinsic mechanisms have been proposed to explain how self-reactive thymocytes commit to the IEL lineage: TCR signals received by IEL precursors (IELp) are thought to be either earlier or stronger than TCR signals received by T-conv precursors, the CD4+ and CD8+ single positive (SP) thymocytes. To distinguish between these hypotheses, we purified thymocyte subsets from mice with a fixed TCRβ chain and deep-sequenced TCRα chain transcripts. We found that the IELp TCRα chain repertoire was at least as diverse as, and clearly distinct from, the CD4SP and CD8SP T-conv repertoires. Based on the chromosomal position of TRAJ gene segments used, the results indicate that early TCR signals are neither necessary nor sufficient for IELp commitment. However, IELp were frequently misdirected into the T-conv lineage in mice with attenuated TCR signaling due to mutations in Zap70. Our data demonstrate that strong TCR signals via Zap70 divert cortical thymocytes into the IEL lineage, thereby preventing a large burden of self-reactive thymocytes from becoming naïve conventional T cells.