title: T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition.
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.
authors.affiliation: Department of Cellular and Molecular Pharmacology and the Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA.
authors.forename: Enfu
authors.identifier: 0000-0001-7876-2783
authors.initials: E
authors.lastname: Hui
authors.affiliation: Department of Cancer Immunology, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Jeanne
authors.identifier: 0000-0001-7969-2449
authors.initials: J
authors.lastname: Cheung
authors.affiliation: Department of Cancer Immunology, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Cellular and Molecular Pharmacology and the Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA.
authors.forename: Xiaolei
authors.identifier: 0000-0001-8696-7922
authors.initials: X
authors.lastname: Su
authors.affiliation: Department of Cellular and Molecular Pharmacology and the Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Taylor
authors.affiliation: Department of Cancer Immunology, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Heidi A
authors.identifier: 0000-0002-9844-6611
authors.initials: HA
authors.lastname: Wallweber
authors.affiliation: Institute for Molecular Engineering, University of Chicago, IL 60637, USA.
authors.forename: Dibyendu K
authors.initials: DK
authors.lastname: Sasmal
authors.affiliation: Institute for Molecular Engineering, University of Chicago, IL 60637, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Cancer Immunology, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Jeong M
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Department of Cancer Immunology, Genentech, South San Francisco, CA 94080, USA. mellman.ira@gene.com ron.vale@ucsf.edu.
authors.forename: Ira
authors.identifier: 0000-0002-6132-7299
authors.initials: I
authors.lastname: Mellman
authors.affiliation: 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.
authors.forename: Ronald D
authors.identifier: 0000-0003-3460-2758
authors.initials: RD
authors.lastname: Vale
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism*; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000628:therapy*; D010766:Phosphorylation; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D018106:CD28 Antigens; D061026:Programmed Cell Death 1 Receptor