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.
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
Induction of tolerance in PD-1 Tg recipients treated with CTLA-4–Ig is ICOS dependent.