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

  • JCI Insight. 2021 Dec 22;6(24):e142909. doi: 10.1172/jci.insight.142909.
Thiago J Borges  1  2 ,  Naoka Murakami  2 ,  Isadora T Lape  1  2 ,  Rodrigo B Gassen  1 ,  Kaifeng Liu  1 ,  Songjie Cai  2 ,  Joe Daccache  2 ,  Kassem Safa  3 ,  Tetsunosuke Shimizu  2 ,  Shunsuke Ohori  2 ,  Alison M Paterson  4  5 ,  Paolo Cravedi  6 ,  Jamil Azzi  2 ,  Peter T Sage  2 ,  Arlene H Sharpe  4  5 ,  Xian C Li  7 ,  Leonardo V Riella  1  2  3
Affiliations
  • 1. Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • 2. Transplantation Research Center, Brigham and Women's Hospital, Boston, Massachusetts, USA.
  • 3. Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • 4. Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, USA.
  • 5. Evergrande Center for Immunologic Diseases and Department of Pathology, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA.
  • 6. Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 7. Immunobiology and Transplant Science Center, Houston Methodist Hospital, Houston, Texas, USA.
PMID: 34752418 DOI: 10.1172/jci.insight.142909
Abstract

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.

Keywords
Costimulation; Immunology; T cells; Tolerance; Transplantation.
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