Programmed 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 γ 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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Supported by a Wellcome Trust Travel Fellowship (to Y. L.) and National Institutes of Health grants AI38310, AI40614 (to A. H. S.) and AI39671, AI41584 and CA84500 (to G. J F.).

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Author notes

    • Arlene H. Sharpe

    These authors contributed equally to this work.


  1. Immunology Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

    • Yvette Latchman
    • , Madhuri Borde
    •  & Arlene H. Sharpe
  2. Genetics Institute, Wyeth-Ayerst Research, Cambridge, MA 02140, USA.

    • Clive R. Wood
    • , Divya Chaudhary
    • , Andrew J. Long
    • , Karen Bourque
    • , Laura L. Carter
    •  & Beatriz M. Carreno
  3. Department of Adult Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

    • Tatyana Chernova
    • , Irene Chernova
    • , Julia A. Brown
    • , Raquel Nunes
    • , Edward A. Greenfield
    • , Vassiliki A. Boussiotis
    • , Nelly Malenkovich
    •  & Gordon J. Freeman
  4. Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.

    • Yoshiko Iwai
    • , Hiroyuki Nishimura
    • , Taku Okazaki
    •  & Tasuku Honjo


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Correspondence to Gordon J. Freeman.

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