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

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.

Small-molecule BCL6 inhibitor protects chronic cardiac transplant rejection and inhibits T follicular helper cell expansion and humoral response

“…To explore the role of Tfhs in chronic cardiac transplant rejection, we established the murine heart transplantation with the BALB/c mice as the donor and B6 mice as the recipient, and treated with CTLA-4-Ig as previous reported ( Figure 2A ) ( Borges et al, 2021 ). As shown in Figure 2B , we found the cardiac grafts could survive for over 4 weeks with the CTLA-4-Ig treatment ( Figure 2B ).…”

Antithymocyte globulin inhibits CD8+ T cell effector functions via the paracrine induction of PDL-1 on monocytes

“…Pre-clinical work by Borges et al revealed a significant increase in graft tolerance of PD-1 overexpressing T cells in a fully MHC-mismatched murine cardiac transplantation model (48). Interestingly, transplantation of PDL-1-knockout donor hearts into PD-1 overexpressing mice resulted in immediate graft rejections strongly underling the importance of the receptor-ligand-pair for peripheral tolerance (48). Moreover, expression of PDL-1 can be found on other cell types besides myeloid cells.…”

“…Binding of IFN-γ to IFN-γR1 modulated expression of PDL-1 on tumor cells and suppressed anti-tumor host immunity leading to disease progression, increased dissemination and worse overall outcome (46).While these regulations are clearly detrimental in oncologic settings, following transplantation modulation of the PD1:PDL-1 axis can significantly improve graft survival and peripheral tolerance (47). Pre-clinical work by Borges et al revealed a significant increase in graft tolerance of PD-1 overexpressing T cells in a fully MHC-mismatched murine cardiac transplantation model (48). Interestingly, transplantation of PDL-1-knockout donor hearts into PD-1 overexpressing mice resulted in immediate graft rejections strongly underling the importance of the receptor-ligand-pair for peripheral tolerance (48).…”

Myocardial-Treg Crosstalk: How to Tame a Wolf

“…As a result, the heart may both prevent futile immune activation at baseline and, following injury, allow a limited response that soon shifts to a pro-resolving phase. Additionally, ligands, such as PD-L1, expressed by myocardial endothelial cells and yet undiscovered targets may contribute to in situ Treg polarization and inhibitory function ( 55 , 56 ).…”