JCI Insight (Dec 2021)

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

  • 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

Journal volume & issue
Vol. 6, no. 24

Abstract

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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.

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