Tolerance induction by liposomes targeting a single CD8 epitope IGRP_206–214 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 2.5mim 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 IGRP206–214 could induce antigen‐specific CD8+ T‐cell‐targeted immune regulation and delay diabetes. Subcutaneous administration of IGRP206–214/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 IGRP206–214/calcitriol liposomes delayed diabetes progression and reduced insulitis. However, when IGRP206–214/calcitriol liposomes were delivered together with 2.5mim/calcitriol liposomes, disease protection was not observed and the regulatory effect of 2.5mim/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.

Islet‐specific CD8+ T cells gain effector function in the gut lymphoid tissues via bystander activation not molecular mimicry

“…Granzyme B expression was increased in the PP on IGRP 206–214 specific cells, suggesting the cells within the PP may be more cytotoxic compared with other tissues (Figure 4b). In order to directly test the cytotoxic capacity of IGRP 206‐214 specific T cells in the various tissues, we performed an in vivo CTL assay as described previously 29 . IGRP 206–214 loaded target cells and control cells were CTV labeled and co‐transferred into NOD mice (Figure 5a, b).…”

Immunology & Cell Biology's Top 10 original research articles 2021–2022

“…Targeting CD8 + T cells by using a CD8 + T-cell epitope led to the transient expansion of antigenspecific CD8 + T cells and, when combined with the immunomodulator, calcitriol, significantly delayed diabetes onset in NOD mice; however, the combination of both CD4 + and CD8 + epitopes in this system abolished this protective effect. 2 The surprising negative impact of this combined approach indicates the complex pathways driving tolerance induction and highlights the need for more studies to carefully dissect the potential of similar multi-epitope strategies to treat autoimmune diseases.…”

“… ICB 's Top 10 from 1 July 2021 to 30 June 2022 (in chronological order of publication): Abers et al 1 . Neutralizing type‐I interferon autoantibodies are associated with delayed viral clearance and intensive care unit admission in patients with COVID‐19. Buckle et al 2 . Tolerance induction by liposomes targeting a single CD8 epitope IGRP 206‐214 in a model of type 1 diabetes is impeded by co‐targeting a CD4 + islet epitope. Vanderven et al 3 .…”

“…• Buckle et al 2 Tolerance induction by liposomes targeting a single CD8 epitope IGRP 206-214 in a model of type 1 diabetes is impeded by co-targeting a CD4 + islet epitope.…”

“…Importantly, the MS therapy, Lemtrada (alemtuzumab; anti-CD52), which depletes specific T-and B-cell populations, led to a restoration in the expression of CD210 and BLNK, both of which are reduced on B cells during MS, suggesting that this MS therapy may resolve relapse-associated B-cell dysregulation. 8 Lastly, the final article by Buckle et al 2 expanded upon previous research demonstrating that liposome delivery of a CD4 + T-cell epitope was tolerogenic and able to protect from diabetes in NOD mice. Targeting CD8 + T cells by using a CD8 + T-cell epitope led to the transient expansion of antigenspecific CD8 + T cells and, when combined with the immunomodulator, calcitriol, significantly delayed diabetes onset in NOD mice; however, the combination of both CD4 + and CD8 + epitopes in this system abolished this protective effect.…”