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PD-L2 is a second ligand for PD-1 and inhibits T cell activation

Abstract

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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Figure 1: Amino acid sequence alignment of murine and human PD-L1 and PD-L2.
Figure 2: Binding of PD-1 to PD-L2.
Figure 3: Comparison of PD-L1 and PD-L2 expression in human and murine tissues.
Figure 4: Inhibition of TCR-mediated responses by PD-L2–PD-1 interaction.
Figure 5: Inhibition of TCR- and CD28-mediated responses by PD-L2–PD-1 and PD-L1–PD-1 interaction.
Figure 6: Engagement of the PD-L–PD1 pathway results in cell cycle arrest and recruitment of SHP-2 but no increase in cell death.

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Acknowledgements

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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Correspondence to Gordon J. Freeman.

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Latchman, Y., Wood, C., Chernova, T. et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2, 261–268 (2001). https://doi.org/10.1038/85330

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