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.

中文翻译：

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抗体介导的混合胰岛素肽靶向新生儿胸腺 Langerin+ 细胞可增强 T 细胞中枢耐受性并延缓自身免疫性糖尿病

胸腺递呈自身抗原对于建立功能性且自我耐受的 T 细胞群至关重要。通过胰腺 β 细胞溶酶体内转肽作用形成的混合肽已被提议作为 1 型糖尿病 (T1D) 中的一类新的自身抗原。虽然尚未探索胸腺中杂合肽的产生，但由于其产生的性质，这被认为是极不可能的。因此，混合肽反应性胸腺细胞可能优先逃避胸腺选择，并对 T1D 进展做出显着贡献。使用抗体-肽缀合系统，我们将 2.5HIP 混合肽靶向胸腺驻留的 Langerin+ 树突状细胞，以增强新生儿早期的胸腺呈现。我们的结果表明，抗Langerin-2.5HIP递送可以增强NOD.BDC2.5小鼠中T细胞对同源胸腺细胞的中枢耐受性。引人注目的是，在新生儿期使用抗 Langerin-2.5HIP 单剂量治疗延迟了 NOD 小鼠的糖尿病发病，这表明在生命早期阶段抗体介导的自身免疫新抗原的递送作为预防自身免疫的治疗选择的潜力疾病。