A microenvironment-driven HLA-II-associated insulin neoantigen elicits persistent memory T cell activation in diabetes
Neetu Srivastava, Anthony N. Vomund, Rongzhen Yu, Orion J. Peterson, Yuqing Yang, David P Turicek, Omar Abousaway, Tiandao Li, Lisa Kain, Pamela Stone, Aisha Ansar, Cristina C. Clement, Siddhartha Sharma, Rima Melhem, Bo Zhang, Chang Liu, Alok V. Joglekar, Hao Hu, Chyi‐Song Hsieh, Laura Campisi, Laura Santambrogio, Luc Teyton, Emil R. Unanue, Ana María Arbeláez, Cheryl F. Lichti, Xiaoxiao Wan
Abstract
The antigenic landscape of autoimmune diabetes reflects a failure to preserve self-tolerance, yet how novel neoantigens emerge in humans remains incompletely understood. Here we designed an immunopeptidomics-based approach to probe HLA-II-bound, islet-derived neoepitopes in patients with type 1 diabetes. We uncovered a Cys→Ser transformation, conserved between mice and humans, that reshapes autoreactivity to insulin at the single-residue level. This transformation, which we call C19S, arises from oxidative remodeling of insulin in stressed pancreatic islets and also occurs in cytokine-activated antigen-presenting cells, contributing to a feed-forward loop of neoepitope formation and presentation. Despite involving just one amino acid, C19S is recognized by HLA-DQ8-restricted, register-specific CD4+ T cells that expand at diabetes onset. These neoepitope-specific CD4+ T cells lack regulatory potential but acquire a poised central memory phenotype that persists throughout disease progression. These findings reveal a distinct, microenvironment-driven route of neoantigen formation that fuels sustained autoreactivity in diabetes. The authors identify a Cys→Ser transformation (C19S) in insulin leading to neoepitope presentation and CD4⁺ T cell autoreactivity in type 1 diabetes. Inflammation and oxidative stress enhanced C19S transformation in β cells and antigen-presenting cells, resulting in C19S-specific CD4⁺ T cells with an activated memory phenotype linked to disease progression.