Studies of individual T cell antigen receptors (TCRs) have shed some light on structural features that underlie self-reactivity. However, the general rules that can be used to predict whether TCRs are self-reactive have not been fully elucidated. Here we found that the interfacial hydrophobicity of amino acids at positions 6 and 7 of the complementarity-determining region CDR3β robustly promoted the development of self-reactive TCRs. This property was found irrespective of the member of the β-chain variable region (V β) family present in the TCR or the length of the CDR3β. An index based on these findings distinguished V β 2+, V β 6+ and V β 8.2+ regulatory T cells from conventional T cells and also distinguished CD4+ T cells selected by the major histocompatibility complex (MHC) class II molecule I-A g7 (associated with the development of type 1 diabetes in NOD mice) from those selected by a non-autoimmunity-promoting MHC class II molecule I-A b. Our results provide a means for distinguishing normal T cell repertoires versus autoimmunity-prone T cell repertoires.
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