New Manuscript in Science Advances: Identification of a type 1 diabetes–associated T cell receptor repertoire signature from the human peripheral blood

We are excited to share our manuscript describing a T1D-associated T cell receptor (TCR) motif, now out in ScienceAdvances. Congratulations to our entire authorship team, led here by first author Puneet Rawat, senior author Todd Brusko, and our long-time computational collaborators Geir Sandve and Victor Greiff.

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

This was a Herculean effort to build a large, well-characterized human sample set, including rich genotyping data, clinical metadata, and sequencing of 2250 TCRβ repertoires from PBMC across the natural history of T1D. Additional samples from the
nPODDiabetes consortium were included to map the motif to distinct T cell subsets from pancreatic draining lymph nodes.

This large dataset, and many additional longitudinal datasets from T1D subjects, are now readily available for download here as Todd Brusko, Aaron Michels, and the T1D AIRR Consortium reported in DiabetologiaJnl here.

This team science effort reflects major contributions from the AIRR Community at iReceptor Gateway, The Human Pancreas Analysis Program (HPAP), Helmsley Charitable Trust, Breakthrough T1D UK, NIH, NIDDK, NIAIDNews, and organized by the
TheSugarScience.

While our primary goal is to define circulating biomarkers from the adaptive immune receptor repertoire in T1D, these large datasets open avenues to optimize AI-driven receptor signatures (learn more here and here) linked to multiple infectious exposure events, and can even help define MHC restrictions shaping the repertoire.

These are exciting times studying the immunobiology of T1D, and analysis of AIRR data will be integral to tracking disease progression and understanding how immunotherapies impact autoimmunity. We are just getting started in this field, and the parameter space will expand to include the B cell receptor (BCR) repertoire and functional data linked with antigen-specificity.

This study represents a larger collaborative effort co-directed with Dr. Aaron Michaels and co-investigators Drs. Maki Nakayama and Mia Smith at the Barbara Davis Center at the University of Colorado. They are making amazing progress defining shared public receptors, identifying insulin-reactive T cell clones from islets and profiling autoreactive B cells.

•Mitchell AM, Baschal EE, McDaniel KA, Fleury T, Choi H, Pyle L, Yu L, Rewers MJ, Nakayama M, Michels AW. Tracking DNA-based antigen-specific T cell receptors during progression to type 1 diabetes. Sci Adv. 2023 Dec 8;9(49):eadj6975.

•Mitchell AM, Baschal EE, McDaniel KA, Simmons KM, Pyle L, Waugh K, Steck AK, Yu L, Gottlieb PA, Rewers MJ, Nakayama M, Michels AW. Temporal development of T cell receptor repertoires during childhood in health and disease. JCI Insight. 2022 Sep 22;7(18):e161885. •

https://pubmed.ncbi.nlm.nih.gov/34611019/ https://pubmed.ncbi.nlm.nih.gov/40117290/ https://pubmed.ncbi.nlm.nih.gov/41411061/