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.
Highlights
Programmed death 1 (PD-1) receptor plays a major inhibitory role in T cell activation via interaction with its ligands PD-L1 and PD-L2, resulting in decreased T cell activation, proliferation, differentiation, and cytokine production [1]
To test the hypothesis that PD-1 overexpression prolongs allograft survival, BALB/c (H-2d) mouse hearts were transplanted into WT or PD-1 Tg B6 (H-2b) mice with or without a single dose of costimulation blockade with CTLA-4–Ig
Rejection tempo was similar in WT and PD-1 Tg recipients not treated with CTLA-4–Ig, with a median survival time (MST) of 7 days
Summary
Programmed death 1 (PD-1) receptor plays a major inhibitory role in T cell activation via interaction with its ligands PD-L1 and PD-L2, resulting in decreased T cell activation, proliferation, differentiation, and cytokine production [1]. PD-1 is upregulated by T cells after antigen-mediated activation of the T cell receptor (TCR), and its expression is decreased once the antigen is cleared [2, 3]. Chronic stimulation of T cells by the antigen leads to high and continuous expression of PD-1, generating an exhausted T cell phenotype [4]. PD-1 is expressed on thymocytes and all CD4+ and CD8+ T cells, including Tregs, exhausted T cells, and memory T cells [5]. In an attempt to induce immune regulation in transplantation, the PD-1/PD-L1 pathway has become an attractive target. PD-1 signaling is critical to protect against rejection in mouse heart [6–9], liver [10], and skin transplant models [11], but the consequence of PD-1 overexpression on T cells is unknown
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