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Science. 2017 Mar 31;355(6332):1428-1433. doi: 10.1126/science.aaf1292. Epub 2017 Mar 9.

T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition.

Author information

1
Department of Cellular and Molecular Pharmacology and the Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA.
2
Department of Cancer Immunology, Genentech, South San Francisco, CA 94080, USA.
3
Institute for Molecular Engineering, University of Chicago, IL 60637, USA.
4
Department of Cancer Immunology, Genentech, South San Francisco, CA 94080, USA. mellman.ira@gene.com ron.vale@ucsf.edu.
5
Department of Cellular and Molecular Pharmacology and the Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA. mellman.ira@gene.com ron.vale@ucsf.edu.

Abstract

Programmed cell death-1 (PD-1) is a coinhibitory receptor that suppresses T cell activation and is an important cancer immunotherapy target. Upon activation by its ligand PD-L1, PD-1 is thought to suppress signaling through the T cell receptor (TCR). By titrating PD-1 signaling in a biochemical reconstitution system, we demonstrate that the co-receptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1-recruited Shp2 phosphatase. We also show that CD28, but not the TCR, is preferentially dephosphorylated in response to PD-1 activation by PD-L1 in an intact cell system. These results reveal that PD-1 suppresses T cell function primarily by inactivating CD28 signaling, suggesting that costimulatory pathways play key roles in regulating effector T cell function and responses to anti-PD-L1/PD-1 therapy.

PMID:
28280247
PMCID:
PMC6286077
DOI:
10.1126/science.aaf1292
[Indexed for MEDLINE]
Free PMC Article

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