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<p>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<sup>+</sup> T cells that expand at diabetes onset. These neoepitope-specific CD4<sup>+</sup> 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.</p>

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A microenvironment-driven HLA-II-associated insulin neoantigen elicits persistent memory T cell activation in diabetes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月28日

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  • 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 Maria Arbelaez,
  • Cheryl F. Lichti,
  • Xiaoxiao Wan

摘要

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.