LAUSR

The calcineurin inhibitor–FK506–is a first‐line immunosuppressant that regulates T cell secretion of IL‐2 and other cytokines. However, the mechanism of its protective effect on target cells and its role on tumour recurrence and interaction with anti‐tumour immune checkpoint inhibitors, such as PD‐L1 blocking, are still unclear. Here, in a murine heart transplantation model, we observed the upregulation of programmed death‐ligand 1 (PD‐L1) expression by FK506 in both dendritic cells (DCs) and allografts. Blocking PD‐L1 during FK506 treatment increased IFN‐γ and TNF‐α expression, enhanced CD4+ and CD8+ T cell proliferation, and suppressed Treg differentiation. Moreover, PD‐L1 decreased T cell infiltration and induced T cell apoptosis in both the spleen and graft. PD‐L1 was not only required in FK506‐mediated immunosuppression but also upregulated by FK506. Treatment with SAFit2, a FKBP51 selective inhibitor, reduced the expression of PD‐L1 on DCs and the grafts and interfered with the immunosuppressive effect of FK506, suggesting that the mechanism depends on FK506‐binding protein (FKBP) 51 expression. Overall, our results add new insights into the role of FK506, not only on T cell cytokine secretion but also on co‐inhibitory molecular regulation and target cell immune privilege.