Nature Immunology
2, 261 - 268 (2001)
doi:10.1038/85330
PD-L2 is a second ligand for PD-1 and inhibits T cell activationYvette Latchman1, Clive R. Wood2, Tatyana Chernova3, Divya Chaudhary2, Madhuri Borde1, Irene Chernova3, Yoshiko Iwai4, Andrew J. Long2, Julia A. Brown3, Raquel Nunes3, Edward A. Greenfield3, Karen Bourque2, Vassiliki A. Boussiotis3, Laura L. Carter2, Beatriz M. Carreno2, Nelly Malenkovich3, Hiroyuki Nishimura4, Taku Okazaki4, Tasuku Honjo4, Arlene H. Sharpe1, 5
& Gordon J. Freeman31
Immunology Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. 2
Genetics Institute, Wyeth-Ayerst Research, Cambridge, MA 02140, USA. 3
Department of Adult Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. 4
Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan. 5
These authors contributed equally to this work.
Correspondence should be addressed to Gordon J. Freeman gordon_freeman@dfci.harvard.eduProgrammed death 1 (PD-1)−deficient mice develop a variety of autoimmune-like diseases, which suggests that this immunoinhibitory receptor plays an important role in tolerance. We identify here PD-1 ligand 2 (PD-L2) as a second ligand for PD-1 and compare the function and expression of PD-L1 and PD-L2. Engagement of PD-1 by PD-L2 dramatically inhibits T cell receptor (TCR)-mediated proliferation and cytokine production by CD4+ T cells. At low antigen concentrations, PD-L2−PD-1 interactions inhibit strong B7-CD28 signals. In contrast, at high antigen concentrations, PD-L2−PD-1 interactions reduce cytokine production but do not inhibit T cell proliferation. PD-L−PD-1 interactions lead to cell cycle arrest in G0/G1 but do not increase cell death. In addition, ligation of PD-1 + TCR leads to rapid phosphorylation of SHP-2, as compared to TCR ligation alone. PD-L expression was up-regulated on antigen-presenting cells by interferon  treatment and was also present on some normal tissues and tumor cell lines. Taken together, these studies show overlapping functions of PD-L1 and PD-L2 and indicate a key role for the PD-L−PD-1 pathway in regulating T cell responses.
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