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

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

  • Science. 2017 Mar 31;355(6332):1428-1433. doi: 10.1126/science.aaf1292.
Enfu Hui 1,  Jeanne Cheung 2,  Jing Zhu 2,  Xiaolei Su 1,  Marcus J Taylor 1,  Heidi A Wallweber 2,  Dibyendu K Sasmal 3,  Jun Huang 3,  Jeong M Kim 2,  Ira Mellman 4,  Ronald D Vale 5
Affiliations

Affiliations

  • 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. [email protected] [email protected].
  • 5 Department of Cellular and Molecular Pharmacology and the Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA. [email protected] [email protected].
PMID: 28280247 DOI: 10.1126/science.aaf1292
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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