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Published online 10 April 2006 doi:10.1084/jem.20051776
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 4, 883-895
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ARTICLE

 Tissue expression of PD-L1 mediates peripheral T cell tolerance

Mary E. Keir1, Spencer C. Liang1, Indira Guleria2, Yvette E. Latchman1, Andi Qipo4, Lee A. Albacker1, Maria Koulmanda4, Gordon J. Freeman3, Mohamed H. Sayegh2, and Arlene H. Sharpe1

1 Department of Pathology and 2 Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, and 3 Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115
4 Islet Transplantation Research Laboratory WH 541, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114

CORRESPONDENCE Arlene H. Sharpe: asharpe{at}rics.bwh.harvard.edu

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.

Abbreviations used: ES, embryonic stem; ILN, inguinal LN; NOD, non-obese diabetic; PD-1, programmed death 1; PD-L, PD-1 ligand; PLN, pancreatic LN; tg, transgenic.

S.C. Liang and I. Guleria contributed equally to this paper.

Y.E. Latchman's present address is Puget Sound Blood Center, Seattle, WA 98104.


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