Activation of T cell checkpoint pathways during β‐cell antigen presentation by engineered dendritic cells promotes protection from type 1 diabetes. Issue 3 (22nd April 2022)

• Record Type: Journal Article
• Authors: Gudi, Radhika R.; Perez, Nicolas; Karumuthil‐Melethil, Subha; Li, Gongbo; Vasu, Chenthamarakshan
• Is Part Of: Immunology. Volume 166:Issue 3(2022)
• Page Start: 341
• Page End: 356
• Publication Date: 2022-04-22
• Subjects: autoimmunity -- beta‐cell antigen -- dendritic cells -- T cell repressor/inhibitory receptors -- T cell tolerance -- type 1 diabetes; Immunology -- Periodicals
• DOI: 10.1111/imm.13476
• Languages: English
• ISSNs: 0019-2805

Abstract

Abstract: 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 β‐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 IFNγ and higher amounts of IL10 and TGFβ1 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. Abstract : Activation of T cell checkpoint pathways during beta‐cell antigen presentation promotes protection from type 1 diabetes