Most T lymphocytes leave the thymus as naïve cells with limited functionality. However, unique populations of T cells, commonly known as innate-like T cells, differentiate into functionally distinct effector subsets during thymic development under the influence of the transcription factor PLZF. Here, we profiled >10,000 differentiating thymic iNKT cells using single-cell RNA sequencing to provide a comprehensive transcriptional landscape of their maturation, function, and fate decision in steady state. We identified Hivep3, a zinc finger transcription factor and adaptor protein, as a key factor that is expressed in early precursors and regulates the postselection proliferative burst, differentiation and functions of iNKT cells. Importantly, we extended these results to other PLZF + innate-like T cell populations, highlighting the unique and common requirement of Hivep3 to the development of all innate-like T cells.

The identification of the peptide epitopes presented by major histocompatibility complex class II molecules (MHCII) that drive the CD4 T cell component of autoimmune diseases has presented a formidable challenge over several decades. In type-1 diabetes (T1D) recent insight into this problem has come from the realization that several of the important epitopes are not directly processed from a protein source, but rather pieced together by fusion of different peptide fragments to create new chimeric epitopes. We have proposed that this fusion is performed by a reverse proteolysis reaction called transpeptidation, occurring during the catabolic turnover of pancreatic proteins when secretory granules fuse with lysosomes. Here we demonstrate that highly antigenic chimeric epitopes for diabetogenic CD4 T cells are produced by digestion of the appropriate fragments of the diabetogenic granule proteins with the lysosomal protease, cathepsin L (CatL). This pathway has implications for how self-tolerance can be broken in T1D and other autoimmune diseases.

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Mature T cells bearing  T cell receptors react with foreign antigens bound to alleles of major histocompatibility complex proteins (MHC) that they were exposed to during their development in the thymus, a phenomenon known as positive selection. The structural basis for positive selection has long been debated. Here, using mice expressing one of two different T cell receptor  chains and various MHC alleles, we show that positive selection-induced MHC bias of T cell receptors is affected both by the germline encoded elements of the T cell receptor  and  chain and, surprisingly, dramatically affected by the non germ line encoded CDR3 of the T cell receptor  chain. Thus, in addition to determining specificity for antigen, the non germline encoded elements of T cell receptors may help the proteins cope with the extremely polymorphic nature of major histocompatibility complex products within the species.