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Antibody-mediated targeting of a hybrid-insulin-peptide towards neonatal thymic Langerin+ cells enhances T cell central tolerance and delays autoimmune diabetes

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posted on 27.05.2022, 14:53 authored by Yong Lin, Jelena Perovanovic, Yuelin Kong, Botond Z. Igyarto, Sandra Zurawski, Dean Tantin, Gerard Zurawski, Maria Bettini, Matthew L. Bettini

  

Thymic presentation of self-antigens is critical for establishing a functional yet self-tolerant T cell population. Hybrid peptides formed through transpeptidation within pancreatic beta cell lysosomes have been proposed as a new class of autoantigens in Type 1 Diabetes (T1D). While the production of hybrid peptides in the thymus has not been explored, due to the nature of their generation, it is thought to be highly unlikely. Therefore, hybrid peptide-reactive thymocytes may preferentially escape thymic selection and contribute significantly to T1D progression. Using an antibody-peptide conjugation system, we targeted the 2.5HIP hybrid peptide towards thymic resident Langerin+ dendritic cells to enhance thymic presentation during the early neonatal period. Our results indicated that anti-Langerin-2.5HIP delivery can enhance T cell central tolerance toward cognate thymocytes in NOD.BDC2.5 mice. Strikingly, a single dose treatment with anti-Langerin-2.5HIP during neonatal period delayed diabetes onset in NOD mice, indicating the potential of antibody-mediated delivery of autoimmune neo-antigens during early stages of life as a therapeutic option in the prevention of autoimmune diseases.

Funding

This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (grant 1R01 DK114456-01A1), Juvenile Diabetes Research Foundation (grant 1-17-JDF-013), The Robert and Janice McNair Foundation, National Institute of Allergy and Infectious Diseases (1R01AI125301, R01AI100873), National Institute of General Medical Sciences (R01GM122778). Cell sorting for scRNA-seq was supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award (CPRIT-RP180672), the NIH (CA125123 and RR024574) and the assistance of Joel M. Sederstrom.

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