Cysteine and hydrophobic residues in CDR3 serve as distinct T-cell self-reactivity indices

The largely stochastic process of T-cell antigen receptor (TCR) gene assembly inevitably produces self-reactive T cells. Although most self-reactive T cells are deleted in the thymus, rare thymocytes survive strong self-antigen engagement and differentiate into type A precursors of CD8??+ intestinal intraepithelial lymphocytes (type A IELps) in the thymic cortex1 or CD4+ forkhead box P3-positive regulatory T (Treg) cells in the thymic medulla.2 Because TCR sequencing revealed amino acid motifs in complementarity-determining region 3 (CDR3) that are enriched in type A IELps or Treg cells,3, 4 we reasoned that the expression of these self-reactive TCR motifs might serve as a biomarker to evaluate T-cell self-tolerance.