Downregulation of cytolytic activity of human effector cells by transgenic expression of human PD‐ligand‐1 on porcine target cells

Cellular rejection is a relevant hurdle for successful pig‐to‐primate xenotransplantion. We have shown previously that the induction of a human anti‐pig T cell response (in vitro activation of CD4⁺ T cells) can be suppressed by the overexpression of human negative costimulatory ligands (e.g. programmed death receptor ligand, PD‐L1) on pig antigen presenting cells. Here, we asked whether PD‐L1 mediated enhancement of negative signaling might also be efficient during the effector phase of human anti‐pig cellular immune responses. The porcine B‐cell line L23 was transfected with human PD‐L1, and clones were selected stably expressing PD‐L1 with low, medium, or high density. Mock‐transfected L23 cells were effectively lysed by human cytotoxic effector cells (IL‐2 activated CD8⁺ T cells and CD56⁺ cells). The lytic potential of the effectors decreased with increasing levels of PD‐L1 and was reduced by about 50% in L23‐PD‐L^high targets. A proportion of activated CD8⁺ effector cells underwent apoptosis when exposed to PD‐L1 expressing L23 cells. These data suggest that the overexpression of PD‐L1 on target cells may (a) trigger negative signals in effector cells that prevent the release of cytolytic molecules and/or (b) induce apoptosis in the attacking effector cells thereby protecting targets from destruction.