ABSTRACT
Type 1 diabetes (T1D) affects a genetically susceptible population that develops autoreactive T cells attacking insulin-producing pancreatic β cells. Increasingly, neoantigens are recognized as critical drivers of this autoimmune response. Here, we report a novel insulin neoepitope generated via post-translational cysteine-to-serine conversion (C>S) in human patients, which is also seen in the autoimmune-prone non-obese diabetic (NOD) mice. This modification is driven by oxidative stress within the microenvironment of pancreatic β cells and is further amplified by T1D-relevant inflammatory cytokines, enhancing neoantigen formation in both pancreatic β cells and dendritic cells. We discover that C>S-modified insulin is specifically recognized by CD4+ T cells in human T1D patients and NOD mice. In humans with established T1D, HLA-DQ8-restricted, C>S-specific CD4+ T cells exhibit an activated memory phenotype and lack regulatory signatures. In NOD mice, these neoepitope-specific T cells can orchestrate islet infiltration and promote diabetes progression. Collectively, these data advance a concept that microenvironment-driven and context-dependent post-translational modifications (PTMs) can generate neoantigens that contribute to organ-specific autoimmunity.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
One author, Dr. Chang Liu, was missing from the author list, which was added. Also, we corrected a typo for Dr. Cheryl Licti's first name.
