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 xenotransplantation. 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.
Plege
Annegret
A
Transplant Laboratory, Department of General, Visceral and Transplantation Surgery, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover, Germany.
Borns
Katja
K
Beer
Lilli
L
Baars
Wiebke
W
Klempnauer
Juergen
J
Schwinzer
Reinhard
R
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D001402:B-Lymphocytes / Q000276:immunology; D060890:B7-H1 Antigen; D019002:CD56 Antigen / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D015536:Down-Regulation; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D034421:Sus scrofa / Q000276:immunology*; D014162:Transfection; D014183:Transplantation, Heterologous / Q000276:immunology*
D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D019002:CD56 Antigen; C522918:NCAM1 protein, human