Identification of a type 1 diabetes-associated T cell receptor repertoire signature from the human peripheral blood

Type 1 diabetes (T1D) is a T cell-mediated disease with a strong immunogenetic human leukocyte antigen (HLA) dependence. HLA allelic influence on the T cell receptor (TCR) repertoire shapes thymic selection and controls activation of diabetogenic clones yet remains largely unresolved in T1D. We sequenced the circulating TCRβ chain repertoire from 2250 HLA-typed participants across three cross-sectional cohorts, including individuals with T1D and healthy related and unrelated controls. We found that HLA risk alleles show higher restriction of TCR repertoires in individuals with T1D. We leveraged deep learning to identify T1D-associated TCR subsequence motifs that were also observed in independent TCR cohorts residing in pancreas-draining lymph nodes of individuals with T1D. Collectively, our data demonstrate T1D-related TCR motif enrichment based on genetic risk, offering a potential metric for autoreactivity and groundwork for TCR-based diagnostics and therapeutics.