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A microenvironment-driven, HLA-II-associated insulin neoantigen elicits persistent memory T cell activation in
Biorxiv : the Preprint Server for Biology
|November 28, 2024
Summary
A novel insulin neoepitope, created by oxidative stress and inflammation, drives autoimmune responses in type 1 diabetes (T1D). This modified insulin is recognized by T cells, promoting disease progression in patients and non-obese diabetic mice.
Area of Science:
- Immunology
- Endocrinology
- Molecular Biology
Background:
- Type 1 diabetes (T1D) involves T cells attacking pancreatic beta cells.
- Neoantigens are increasingly recognized as key drivers of autoimmune responses in T1D.
- Post-translational modifications (PTMs) can alter self-antigens, potentially triggering autoimmunity.
Purpose of the Study:
- To identify novel neoantigens involved in T1D pathogenesis.
- To investigate the role of post-translational modifications in generating T1D-associated neoantigens.
- To characterize the T cell response to modified insulin neoepitopes.
Main Methods:
- Analysis of insulin neoepitopes in human T1D patients and non-obese diabetic (NOD) mice.
- Investigating the role of oxidative stress and inflammatory cytokines in neoantigen formation.
- Characterizing T cell recognition of C>S-modified insulin using immunological assays.
- Assessing the impact of neoepitope-specific T cells on diabetes progression in NOD mice.
Main Results:
- A novel insulin neoepitope, generated by cysteine-to-serine conversion (C>S), was identified in human T1D and NOD mice.
- Oxidative stress and inflammatory cytokines amplify C>S neoantigen formation in beta cells and dendritic cells.
- CD4+ T cells in T1D patients and NOD mice specifically recognize C>S-modified insulin.
- C>S-specific CD4+ T cells in T1D patients show an activated memory phenotype, while in NOD mice, they promote insulitis and diabetes.
Conclusions:
- Microenvironment-driven PTMs, such as C>S conversion, can generate critical neoantigens in T1D.
- These neoantigens elicit autoreactive T cell responses contributing to organ-specific autoimmunity.
- Understanding neoantigen generation pathways offers potential therapeutic targets for T1D.
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