| Autor: |
Srivastava N, Vomund AN, Peterson OJ, Abousaway O, Li T, Kain L, Stone P, Clement CC, Sharma S, Zhang B, Liu C, Joglekar AV, Campisi L, Hsieh CS, Santambrogio L, Teyton L, Arbelaez AM, Lichti CF, Wan X |
| Jazyk: |
angličtina |
| Zdroj: |
BioRxiv : the preprint server for biology [bioRxiv] 2024 Nov 13. Date of Electronic Publication: 2024 Nov 13. |
| DOI: |
10.1101/2024.11.07.622538 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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