<p>Pancreatic islet transplantation offers a potential cure for autoimmune type 1 diabetes (T1D) but requires immunosuppression to prevent recurrent, T cell-mediated autoimmunity. Antigen-specific immunotherapy is a targeted alternative that induces peripheral tolerance in autoreactive T cells without broad immunosuppression. Tolerance induction with antigen-specific therapies may induce dominant tolerance, extending to T cell clones other than those targeted by the therapy. However, the mechanism of this suppression remains unclear. Using pancreatic islet transplantation in NOD mice, we show that induction of tolerance to a CD4⁺ T cell hybrid insulin peptide neoepitope reprograms the fate of antigen-specific CD8⁺ T cells within the grafts. Induction of tolerance to a single hybrid insulin peptide transiently protected islet grafts from autoimmune destruction, and graft survival could be extended with continued therapeutic dosing. Treatment limited a cytolytic/interferon-stimulated differentiation program in antigen-specific CD8⁺ T cells and reduced TCR avidity within grafts. This was mediated in part by IL-10-producing regulatory CD4⁺ T cells that suppressed dendritic cell activation. IL-10 blockade reversed these effects, restoring CD8⁺ T cell differentiation, as well as the licensing of dendritic cells. These findings reveal an IL-10-dependent mechanism by which CD4⁺ T cell-targeted immunotherapy restrains pathogenic CD8⁺ T cell fates through the suppression of dendritic cells in islet grafts.</p>