Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation

By G. Freeman, A. Long, Yoshiko Iwai, Karen Bourque, T. Chernova, H. Nishimura, L. Fitz, Nelly Malenkovich, Taku Okazaki, M. Byrne and 9 more. Journal of Experimental Medicine, 2000

5,135 citations recorded by the source corpus.

PD-1 is an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells. Mice deficient in PD-1 exhibit a breakdown of peripheral tolerance and demonstrate multiple autoimmune features. We report here that the ligand of PD-1 (PD-L1) is a member of the B7 gene family. Engagement of PD-1 by PD-L1 leads to the inhibition of T cell receptor–mediated lymphocyte proliferation and cytokine secretion. In addition, PD-1 signaling can inhibit at least suboptimal levels of CD28-mediated costimulation. PD-L1 is expressed by antigen-presenting cells, including human peripheral blood monocytes stimulated with interferon γ, and activated human and murine dendritic cells. In addition, PD-L1 is expressed in nonlymphoid tissues such as heart and lung. The relative levels of inhibitory PD-L1 and costimulatory B7-1/B7-2 signals on antigen-presenting cells may determine the extent of T cell activation and consequently the threshold between tolerance and autoimmunity. PD-L1 expression on nonlymphoid tissues and its potential interaction with PD-1 may subsequently determine the extent of immune responses at sites of inflammation.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/580e84d654cdf9007f212772912b45344d51170a

How researchers see this paper

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In Immunology

1. Lieping Chen
2. D. Pardoll
3. G. Freeman
4. W. Zou
5. E. Wherry
6. Arlene H. Sharpe
7. Rafi Ahmed
8. J. Wolchok

In Oncology

1. Lieping Chen
2. D. Pardoll
3. G. Freeman
4. Arlene H. Sharpe
5. E. Wherry
6. J. Wolchok
7. W. Zou
8. James P. Allison

Citations in the corpus

• Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018, background): “PD-1 activity is therefore only relevant during simultaneous T cell activation, as its signal transduction can only come into effect during TCRdependent signaling (39, 41, 48).”
• Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity (2012, neutral): “The basis for this physiology is that the ligands for PD-1, B7-H1/PD-L1 [10,11] and B7-DC/ PD-L2 [12,13], are up-regulated in response to inflammation.”
• Inhibitory B7-family molecules in the tumour microenvironment (2008, background): “Programmed cell death 1 (PD-1; also known as CD279) has been subsequently identified as a counter-receptor for B7-H1 (Ref”
• Immune Checkpoint Blockade in Cancer Therapy. (2015, background): “When engaged by ligand, through phosphatase activity, PD-1 inhibits kinase signaling pathways that normally lead to T-cell activation.(25) Mice deficient in PD-1 have a distinct autoimmune phenotype from mice deficient in CTLA-4.”
• PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression (2017, positive): “Engagement of the PD-1 receptor on T cells by PDL1 leads to the suppression of T-cell proliferation, cytokine release, and cytolytic activity, whereas blockade of coinhibitory ligation withmAbs, such as PD-L1 or PD-1 antibodies, restores Tcell function and increases therapeutic efficacy (10, 11).”