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

The autoimmune disease, type 1 diabetes, is predominantly mediated by CD8 cytotoxic T cell destruction of islet beta-cells, of which IGRP 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 together with NF-κB inhibitor calcitriol induced regulatory T cells and protected from diabetes in NOD mice. Here we investigated whether the same system delivering IGRP could induce antigen-specific CD8 T cell targeted immune regulation and delay diabetes. Subcutaneous administration of IGRP /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 IFNγ production and cytotoxicity. Concordantly, a short course of IGRP /calcitriol liposomes delayed diabetes progression and reduced insulitis. However, when IGRP /calcitriol liposomes were delivered together with 2.5 /calcitriol liposomes, disease protection was not observed and the regulatory effect of 2.5 /calcitriol liposomes was abrogated. Thus, tolerogenic liposomes that target either a dominant CD8 or CD4 T cell islet epitope can delay diabetes progression but combining multiple epitopes does not enhance protection.