Endothelial Stromal PD-L1 Modulates CD8+ T Cell Infiltration after Heart Transplantation

Abstract

Purpose Heart transplantation is the only definitive treatment for end-stage heart failure. The role of checkpoint axes in transplantation has been partially addressed in animal models, but not in humans. Occurrence of fulminant myocarditis with allorejection-like immunologic features in patients under anti-PD1 treatment suggests a key role of the PD-1/PD-L1 axis in cardiac immune homeostasis. Methods We cross-sectionally studied 23 heart transplant patients undergoing surveillance endomyocardial biopsy (EMB). EMB tissue and peripheral blood mononuclear cells (PBMC) were analyzed by flow cytometry. Multivariate logistic regression analyses including demographic, clinical and hemodynamic parameters were performed. Murine models were used to evaluate the impact of PD-L1 endothelial graft expression in allorejection. Results We found that myeloid cells dominate the composition of the graft leukocyte compartment in most patients, however with variable T cells frequencies that in few patients were the main infiltrating population. The CD4:CD8 T cells ratios were between 0 and 1.5. The proportion of PD-L1 expressing cells in graft endothelial cells, fibroblasts and myeloid leukocytes ranged from negligible up to 60%. We found a significant inverse correlation following an exponential decay pattern between a proportion of PD-L1+HLA-DR+ endothelial cells and proportion of CD8+ T cells. PD-L1 expression and leukocyte patterns were independent of demographic, clinical and hemodynamic parameters. We confirmed the importance of PD-L1 expression by endothelial cells in a murine model of fully allogeneic heart transplant. We found that Tie2Crepdl1fl/fl grafts lacking PD-L1 in endothelial cells were rejected significantly faster than Tie2Cre controls. Conclusion Loss of graft endothelial PD-L1 expression may play a permissive role toward CD8+ T cell infiltration in human heart transplantation. Murine model results suggest that indeed loss of graft endothelial PD-L1 may facilitates alloresponses, and thus potentially play a role in heart transplant rejection.