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T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition
E. Hui, J. Cheung, J. Zhu, X. Su, M.J. Taylor, H.A. Wallweber, , J. Huang, J.M. Kim, I. MellmanShow More
Published in American Association for the Advancement of Science
PMID: 28280247
Volume: 355
Issue: 6332
Pages: 1428 - 1433
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 coreceptor 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.
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PublisherData powered by TypesetAmerican Association for the Advancement of Science