Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis.
Interactions between CD8+ T cells and endothelial cells are important in both protective and pathologic immune responses. Endothelial cells regulate the recruitment of CD8+ T cells into tissues, and the activation of CD8+ T cells by antigen presentation and costimulatory signals. PD-L1 and PD-L2 are recently described B7-family molecules which bind to PD-1 on activated lymphocytes and down-regulate T cell activation. We found that PD-L1 is expressed on interferon-gamma stimulated cultured human and mouse endothelial cells, while PD-L2 was found on stimulated human but not mouse endothelial cells. Expression was further up-regulated by TNF-alpha. Antibody blockade of endothelial cell PD-L1 and PD-L2 enhanced endothelial cell costimulation of PHA-activated human CD8+ T cells. Antibody blockade of mouse endothelial cell PD-L1 enhanced both IFN-gamma secretion and cytolytic activity of CD8+ T cells in response to endothelial cell antigen presentation. These results show that IFN-gamma activated endothelial cells can inhibit T cell activation via expression of the immunoinhibitory PD-L1 and PD-L2 molecules. Endothelial expression of PD-ligands would allow activation and extravasation of T cells without excessive vessel damage. Our findings highlight a potentially important pathway by which endothelial cells down-regulate CD8+ T cell-mediated immune responses.
The Immunology Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Nancy
N
Rodig
Timothy
T
Ryan
Jessica A
JA
Allen
Hong
H
Pang
Nir
N
Grabie
Tatyana
T
Chernova
Edward A
EA
Greenfield
Spencer C
SC
Liang
Arlene H
AH
Sharpe
Andrew H
AH
Lichtman
Gordon J
GJ
Freeman
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins / Q000096:biosynthesis / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D051379:Mice; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D061027:Programmed Cell Death 1 Ligand 2 Protein
D015703:Antigens, CD; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins; C423236:CD274 protein, human; C498919:Cd274 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C556977:PDCD1LG2 protein, human; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein