Tolerance induction by liposomes targeting a single CD8 epitope IGRP206-214 in a model of type 1 diabetes is impeded by co-targeting a CD4+ islet epitope

Abstract

The autoimmune disease type 1 diabetes is predominantly mediated by CD8⁺ cytotoxic T-cell destruction of islet beta cells, of which islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)_206-214 is a dominant target antigen specificity. Previously, we found that a liposome-based antigen-specific immunotherapy encapsulating the CD4⁺ T-cell islet epitope 2.5_mim together with the nuclear factor-κB inhibitor calcitriol induced regulatory T cells and protected from diabetes in NOD mice. Here we investigated whether the same system delivering IGRP_206-214 could induce antigen-specific CD8⁺ T-cell-targeted immune regulation and delay diabetes. Subcutaneous administration of IGRP_206-214 /calcitriol liposomes transiently activated and expanded IGRP-specific T-cell receptor transgenic 8.3 CD8⁺ T cells. Liposomal co-delivery of calcitriol was required to optimally suppress endogenous IGRP-specific CD8⁺ T-cell interferon-γ production and cytotoxicity. Concordantly, a short course of IGRP_206-214 /calcitriol liposomes delayed diabetes progression and reduced insulitis. However, when IGRP_206-214 /calcitriol liposomes were delivered together with 2.5_mim /calcitriol liposomes, disease protection was not observed and the regulatory effect of 2.5_mim /calcitriol liposomes was abrogated. Thus, tolerogenic liposomes that target either a dominant CD8⁺ or a CD4⁺ T-cell islet epitope can delay diabetes progression but combining multiple epitopes does not enhance protection.

Keywords: 1α,25-Dihydroxyvitamin D3; CD8 T-cell tolerance; NOD mice; antigen-specific immunotherapy; autoantigen; autoimmunity; calcitriol; liposome; regulation; type 1 diabetes; vitamin D3.