Tolerance induction by liposomes targeting a single CD8 epitope IGRP 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 islet-specific glucose-6-phosphatase catalytic subunit-related protein (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 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 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 interferon-γ 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 a CD4 T-cell islet epitope can delay diabetes progression but combining multiple epitopes does not enhance protection.