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

  • Author(s): Hui, Enfu
  • Cheung, Jeanne
  • Zhu, Jing
  • Su, Xiaolei
  • Taylor, Marcus J
  • Wallweber, Heidi A
  • Sasmal, Dibyendu K
  • Huang, Jun
  • Kim, Jeong M
  • Mellman, Ira
  • Vale, Ronald D
  • et al.
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.

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