Activation of T cell checkpoint pathways during beta-cell antigen presentation by engineered dendritic cells promotes protection from type 1 diabetes

Defective immune regulation has been recognized in type 1 diabetes (T1D). Immune regulatory T cell check-point receptors, which are generally upregulated on activated T cells, have been the molecules of attention as therapeutic targets for enhancing immune response in tumour therapy. Here, we show that pancreatic beta-cell antigen (BcAg) presentation by engineered tolerogenic dendritic cells (tDCs) that express CTLA4 selective ligand (B7.1wa) or a combination of CTLA4, PD1 and BTLA selective ligands (B7.1wa, PD-L1 and HVEM-CRD1 respectively; multiligand-DCs) causes an increase in regulatory cytokine and T cell (Treg) responses and suppression of the effector T cell function as compared with engineered control-DCs. Non-obese diabetic mice treated with BcAg-pulsed CTLA4-ligand-DCs and multiligand-DCs at pre-diabetic and early-hyperglycaemic stages showed significantly lower degree of insulitis, higher frequencies of insulin-positive islets, profound delay in and reversal of hyperglycaemia for a significant duration. Immune cells from the tDC-treated mice not only produced lower amounts of IFN gamma and higher amounts of IL10 and TGF beta 1 upon BcAg challenge, but also failed to induce hyperglycaemia upon adoptive transfer. While both CTLA4-ligand-DCs and multiligand-DCs were effective in inducing tolerance, multiligand-DC treatment produced an overall higher suppressive effect on effector T cell function and disease outcome. These studies show that enhanced engagement of T cell checkpoint receptors during BcAg presentation can modulate T cell function and suppress autoimmunity and progression of the disease in T1D.

Automated summary

Enhancing T cell checkpoint receptor engagement during antigen presentation can modulate T cell function, suppress autoimmunity, and inhibit disease progression in T1D.