Tissue expression of PD-L1 mediates peripheral T cell tolerance.
Programmed death 1 (PD-1), an inhibitory receptor expressed on activated lymphocytes, regulates tolerance and autoimmunity. PD-1 has two ligands: PD-1 ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells; and PD-L2, which is restricted to macrophages and dendritic cells. To investigate whether PD-L1 and PD-L2 have synergistic or unique roles in regulating T cell activation and tolerance, we generated mice lacking PD-L1 and PD-L2 (PD-L1/PD-L2(-/-) mice) and compared them to mice lacking either PD-L. PD-L1 and PD-L2 have overlapping functions in inhibiting interleukin-2 and interferon-gamma production during T cell activation. However, PD-L1 has a unique and critical role in controlling self-reactive T cells in the pancreas. Our studies with bone marrow chimeras demonstrate that PD-L1/PD-L2 expression only on antigen-presenting cells is insufficient to prevent the early onset diabetes that develops in PD-L1/PD-L2(-/-) non-obese diabetic mice. PD-L1 expression in islets protects against immunopathology after transplantation of syngeneic islets into diabetic recipients. PD-L1 inhibits pathogenic self-reactive CD4+ T cell-mediated tissue destruction and effector cytokine production. These data provide evidence that PD-L1 expression on parenchymal cells rather than hematopoietic cells protects against autoimmune diabetes and point to a novel role for PD-1-PD-L1 interactions in mediating tissue tolerance.
Keir
Mary E
ME
Department of Pathology, Brigham and Women's Hospital and Children's Hospital Boston, MA 02115, USA.
Liang
Spencer C
SC
Guleria
Indira
I
Latchman
Yvette E
YE
Qipo
Andi
A
Albacker
Lee A
LA
Koulmanda
Maria
M
Freeman
Gordon J
GJ
Sayegh
Mohamed H
MH
Sharpe
Arlene H
AH
D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D060890:B7-H1 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009928:Organ Specificity / Q000276:immunology; D010455:Peptides / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D061027:Programmed Cell Death 1 Ligand 2 Protein; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D016207:Cytokines; D008562:Membrane Glycoproteins; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D007371:Interferon-gamma