Pigs expressing the human inhibitory ligand PD‐L1 (CD 274) provide a new source of xenogeneic cells and tissues with low immunogenic properties

Background The programmed cell death‐1 (PD‐1, CD279)/PD‐Ligand1 (PD‐L1, CD274) receptor system is crucial for controlling the balance between immune activation and induction of tolerance via generation of inhibitory signals. Expression of PD‐L1 is associated with reduced immunogenicity and renders cells and tissues to an immune‐privileged/tolerogenic state. Methods To apply this concept for clinical xenotransplantation, we generated human (h)PD‐L1 transgenic pigs and characterized expression and biological function of the transgene at the cellular level. Results The hPD‐L1 was detected in kidney, heart, and pancreas. In addition, peripheral blood mononuclear cells (PBMC), cultured fibroblasts, and endothelial cells were hPD‐L1 positive (hPD‐L1+). The hPD‐L1 levels were increased by the treatment of transgenic cells with human cytokines (eg, TNF‐α), suggesting a regulatable mode of transgene expression. Compared to cells from wild‐type pigs, hPD‐L1+ PBMC had a significantly reduced capacity to stimulate proliferation of human CD4+ T cells. Moreover, fibroblasts from hPD‐L1 transgenic pigs were partially protected from cell‐mediated lysis by human cytotoxic effector cells. Conclusions These data indicate a low immunogenic, immune‐protected status of cells from hPD‐L1 transgenic pigs. The integration of the hPD‐L1 concept into existing multi‐transgenic pigs is promising to achieve long‐term survival of porcine xenografts in non‐human primate recipients.