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[Report] T cell costimulatory receptor CD28 is a primary target for PD-1–mediated inhibition

ScienceNOW - Fetched: March 31st, 2017, 3:00pm UTC

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. Authors: Enfu Hui, Jeanne Cheung, Jing Zhu, Xiaolei Su, Marcus J. Taylor, Heidi A. Wallweber, Dibyendu K. Sasmal, Jun Huang, Jeong M. Kim, Ira Mellman, Ronald D. Vale

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