Antibody-Mediated Targeting of a Hybrid Insulin Peptide Toward Neonatal Thymic Langerin-Positive Cells Enhances T-Cell Central Tolerance and Delays Autoimmune Diabetes

Abstract

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.

Increased TCR signaling in regulatory T cells is disengaged from TCR affinity

“…Our observations suggest a general lack of diabetogenicity among islet-specific TCRs, which is consistent with an idea that diabetes is driven by few initiator clones that preferentially recognize islet neoantigens not expressed in the thymus, and therefore lack tTreg development of the same specificity [30][31][32] . However, if islet antigen specific tTregs are skewed towards increased affinity for antigens expressed in the thymus, such as insulin, we would expect Treg repertoire to be enriched in TCRs with high capacity for beta cell destruction, which we did not observe.…”

“…CD25-Foxp3+ and CD25+Foxp3-thymic Treg precursors exhibit distinct TCR repertoires, suggesting development in response to different peptide ligands 55 . Expansion of thymic antigenic niche preferentially leads to CD25-Foxp3+ Treg pathway of development 31 , suggesting that low affinity self-reactive TCRs associated with increased antigenic niche follow the CD25-Foxp3+ trajectory. Therefore, Foxp3 expression might be an important factor for increased Treg sensitivity for antigen.…”