Contribution of a Hybrid Insulin Peptide-reactive T cell to Diabetes progression in the NOD mouse
| Autor: | Yong Lin, Yuelin Kong, Botond Z Igyarto, Gerard Zurawski, Sandra Zurawski, Maria Bettini, Matthew Bettini |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 206:51.08-51.08 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Type 1 Diabetes (T1D) is a T cell-mediated autoimmune disease characterized by the immune destruction of pancreatic β cells. The search for natural equivalents to the mimetopes that can stimulate diabetogenic T cell clones from the Non-Obese Diabetic (NOD) mouse model of T1D led to the realization that hybrid peptides (HP) formed by the joining of β cell granule protein-derived peptide fragments are highly stimulatory to some clones. These hybrid peptides were later identified in vivo and proposed as a new class of post-translationally modified autoantigens mediating this disease. Recent data suggest high concentrations of these proteins in β cell lysosomes during granule turnover can lead to the hybridization of peptide fragments which may then be presented on MHC molecules. In the thymus, medullary thymic epithelial cells (mTECs) mediate T cell tolerance through promiscuous gene expression, but may not mediate HP-reactive T cell tolerance. We hypothesize that HP-reactive T cells preferentially escape the thymus and contribute significantly to T1D progression. We attempted to enhance T cell central tolerance to 2.5HIP, a hybrid insulin peptide formed from Proinsulin and Chromogranin A, the only two antigens known to be critical for T1D progression in the NOD mice, to better understand its impact on T1D incidence. Using an antibody-peptide conjugation system, we targeted 2.5HIP to a subset of thymic resident DCs to enhance presentation of 2.5HIP in early neonatal thymus. In neonatal BDC2.5 TCR-transgenic mice we found that a single dose of antibody-2.5HIP enhanced antigen-specific thymocyte apoptosis and regulatory T cell development. Importantly, a single dose in wild-type neonates resulted in a significant delay of diabetes onset. |
| Databáze: | OpenAIRE |
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