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

Puneet Rawat; Melanie R. Shapiro; Leeana D. Peters; Michael Widrich; Koshlan Mayer-Blackwell; Keshav Motwani; Milena Pavlović; Ghadi al Hajj; Amanda L. Posgai; Chakravarthi Kanduri; Giulio Isacchini; Maria Chernigovskaya; Lonneke Scheffer; Kartik Motwani; Leandro Octavio Balzano-Nogueira; Camryn M. Pettenger-Willey; Sebastiaan Valkiers; Laura M. Jacobsen; Michael J. Haller; Desmond Schatz; Clive Henry Wasserfall; Ryan O. Emerson; Andrew J. Fiore-Gartland; Mark A. Atkinson; Gnter Klambauer; Geir Kjetil Sandve; Victor Greiff; Todd M. Brusko

doi:10.1126/sciadv.adx7448

Genetic & Genomic MedicineScience AdvancesFeb 13, 2026

Peer-reviewed journal article

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

Puneet Rawat iD, Melanie R. Shapiro iD, Leeana D. Peters iD, Michael Widrich iD, Koshlan Mayer-Blackwell iD, Keshav Motwani iD, Milena Pavlović iD, Ghadi al Hajj, Amanda L. Posgai iD, Chakravarthi Kanduri iD, Giulio Isacchini iD, Maria Chernigovskaya iD, Lonneke Scheffer iD, Kartik Motwani iD, Leandro Octavio Balzano-Nogueira iD, Camryn M. Pettenger-Willey iD, Sebastiaan Valkiers iD, Laura M. Jacobsen iD, Michael J. Haller iD, Desmond Schatz iD, Clive Henry Wasserfall iD, Ryan O. Emerson, Andrew J. Fiore-Gartland iD, Mark A. Atkinson iD, Gnter Klambauer, , Todd M. Brusko iD

Abstract

Type 1 Diabetes (T1D) is a T-cell mediated disease with a strong immunogenetic 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 TCR{beta} chain repertoire from 2250 HLA-typed individuals across three cross-sectional cohorts, including T1D patients, and healthy related and unrelated controls. We found that HLA risk alleles show higher restriction of TCR repertoires in T1D individuals. 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 T1D individuals. Collectively, our data demonstrate T1D-related TCR motif enrichment based on genetic risk, offering a potential metric for autoreactivity and basis for TCR-based diagnostics and therapeutics.

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