[ab] T‐cell receptors with a central CDR 3 cysteine are enriched in CD [8aa] intraepithelial lymphocytes and their thymic precursors

The thymus plays a crucial role in immune tolerance by exposing developing T cells (thymocytes) to a myriad of self‐antigens. Strong T‐cell receptor (TCR ) engagement induces tolerance in self‐reactive thymocytes by stimulating apoptosis or selection into specialized T‐cell lineages, including intestinal TCR αβ+ CD 8αα+ intraepithelial lymphocytes (IEL ). TCR ‐intrinsic amino acid motifs that can be used to predict whether a TCR will be strongly self‐reactive remain elusive. Here, a novel TCR sequence alignment approach revealed that T‐cell lineages in C57BL /6 mice had divergent usage of cysteine within two positions of the amino acid at the apex of the complementarity‐determining region 3 (CDR 3) of the TCR α or TCR β chain. Compared to pre‐selection thymocytes, central CDR 3 cysteine usage was increased in IEL and Type A IEL precursors (IEL p) and markedly decreased in Foxp3+ regulatory T cells (T‐reg) and naïve T cells. These findings reveal a TCR ‐intrinsic motif that distinguishes Type A IEL p and IEL from T‐reg and naïve T cells.