Antigen-specific immunotherapy with a CD4 hybrid insulin peptide neoepitope arrests CD8 T cell differentiation in islet grafts

Antigen‐specific immunotherapies aim to induce peripheral tolerance in autoreactive T cells without the collateral risks of broad immunosuppression. In type 1 diabetes, certain class II HLA molecules strongly predict disease risk, indicating the centrality of CD4 T cell epitopes in disease. However, CD8 T cells targeting islet-antigens are predominant in human islet infiltrates and critical for disease progression. Understanding how peripheral tolerance induction to CD4 peptide autoantigens can generate the suppression of antigen-specific CD8 T cells is still not entirely understood. Here, we show that nanoparticles conjugated to a single CD4 T cell epitope, a hybrid insulin peptide, can reshape the fate of antigen‐specific CD8 T cells in islet grafts. Induction of tolerance arrested the functional differentiation of antigen-specific CD8 T cells and restricted their TCR repertoire towards a lower‐avidity public TCR. Antigen-specific CD8 T cells are arrested in part by the expansion of interleukin-10 (IL-10)-producing antigen-specific CD4 regulatory populations that function through indirect suppression of dendritic cell licensing in grafts. Neutralization of IL-10 during hybrid insulin peptide tolerance induction abrogates graft protection, restores CD8 effector differentiation and TCR affinity, and rescues dendritic cell licensing, establishing an IL-10 dependent suppression axis. These findings help explain how antigen‐specific therapy to a single CD4 hybrid insulin peptide epitope can arrest autoreactive CD8 T cell effector fates in transplanted islets, prolonging graft survival.