Overexpression of PD-1 on T cells promotes tolerance in cardiac transplantation via ICOS-dependent mechanisms

• DOI: 10.1172/jci.insight.142909
• Publication Date: 2021-11-09T17:54:21Z
• Authors: Thiago J. Borges; Naoka Murakami; Isadora T. Lape; Rodrigo B. Gassen; Kaifeng Liu; Songjie Cai; Joe Daccache; Kassem Safa; Tetsunosuke Shimizu; Shunsuke Ohori; Alison M. Paterson; Paolo Cravedi; Jamil Azzi; Peter T. Sage; Arlene H. Sharpe; Xian C. Li; Leonardo V. Riella
• Keywords: 0301 basic medicine; Transplantation; T-Lymphocytes; Immunology; Programmed Cell Death 1 Receptor; R; Survival Analysis; 3. Good health; Inducible T-Cell Co-Stimulator Protein; Disease Models, Animal; Mice; 03 medical and health sciences; Medicine; Animals; Heart Transplantation; Humans; Research Article

The programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway is a potent inhibitory pathway involved in immune regulation and is a potential therapeutic target in transplantation. In this study, we show that overexpression of PD-1 on T cells (PD-1 Tg) promotes allograft tolerance in a fully MHC-mismatched cardiac transplant model when combined with costimulation blockade with CTLA-4-Ig. PD-1 overexpression on T cells also protected against chronic rejection in a single MHC II-mismatched cardiac transplant model, whereas the overexpression still allowed the generation of an effective immune response against an influenza A virus. Notably, Tregs from PD-1 Tg mice were required for tolerance induction and presented greater ICOS expression than those from WT mice. The survival benefit of PD-1 Tg recipients required ICOS signaling and donor PD-L1 expression. These results indicate that modulation of PD-1 expression, in combination with a costimulation blockade, is a promising therapeutic target to promote transplant tolerance.