T cell receptor β-chains display abnormal shortening and repertoire sharing in type 1 diabetes

Defects in T cell receptor (TCR) repertoire are proposed to predispose to autoimmunity. Here we show, by analyzing >2×108 TCRB sequences of circulating naive, central memory, reg- ulatory and stem cell-like memory CD4+ T cell subsets from patients with type 1 diabetes and healthy donors, that patients have shorter TCRB complementarity-determining region 3s (CDR3), in all cell subsets, introduced by increased deletions/reduced insertions during VDJ rearrangement. High frequency of short CDR3s is also observed in unproductive TCRB sequences, which are not subjected to thymic culling, suggesting that the shorter CDR3s arise independently of positive/negative selection. Moreover, TCRB CDR3 clonotypes expressed by autoantigen-specific CD4+ T cells are shorter compared with anti-viral T cells, and with those from healthy donors. Thus, early events in thymic T cell development and repertoire generation are abnormal in type 1 diabetes, which suggest that short CDR3s increase the potential for self-recognition, conferring heightened risk of autoimmune disease. We sorted CD4+ T cell subsets (central memory, naive cells) from 14 individuals newly diagnosed with type 1 diabetes and 14 healthy individuals matched by sex and age. Additionaly, for 8 individuals from each group we sorted regulatory T cells and T-memory stem cells (Tscm). We isolated total RNA from sorted cells and Adaptive Biotechnologies performed TRB sequencing from it *************************************************************** Raw data generated by Adaptive Biotechnologies. Submitter states that Adaptive Biotechnologies does not release raw data. ***************************************************************