2. Academic Validation
  3. Overexpression of PD-1 on T cells promotes tolerance in cardiac transplantation via ICOS-dependent mechanisms

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

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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