title: Strength of PD-1 signaling differentially affects T-cell effector functions.
abstract: High surface expression of programmed death 1 (PD-1) is associated with T-cell exhaustion; however, the relationship between PD-1 expression and T-cell dysfunction has not been delineated. We developed a model to study PD-1 signaling in primary human T cells to study how PD-1 expression affected T-cell function. By determining the number of T-cell receptor/peptide-MHC complexes needed to initiate a Ca(2+) flux, we found that PD-1 ligation dramatically shifts the dose-response curve, making T cells much less sensitive to T-cell receptor-generated signals. Importantly, other T-cell functions were differentially sensitive to PD-1 expression. We observed that high levels of PD-1 expression were required to inhibit macrophage inflammatory protein 1 beta production, lower levels were required to block cytotoxicity and IFN-γ production, and very low levels of PD-1 expression could inhibit TNF-α and IL-2 production as well as T-cell expansion. These findings provide insight into the role of PD-1 expression in enforcing T-cell exhaustion and the therapeutic potential of PD-1 blockade.
authors.affiliation: Department of Microbiology and Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Wei
authors.forename: Shi
authors.initials: S
authors.lastname: Zhong
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Ma
authors.forename: Hong
authors.initials: H
authors.lastname: Kong
authors.forename: Andrew
authors.initials: A
authors.lastname: Medvec
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Michelle
authors.initials: M
authors.lastname: Krogsgaard
authors.forename: James L
authors.initials: JL
authors.lastname: Riley
mesh_terms: D020013:Calcium Signaling / Q000276:immunology; D002478:Cells, Cultured; D054407:Chemokine CCL4 / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000378:metabolism; D018448:Models, Immunological; D061026:Programmed Cell Death 1 Receptor / Q000737:chemistry / Q000502:physiology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C066507:CCL4 protein, human; D054407:Chemokine CCL4; C508594:IL2 protein, human; D007376:Interleukin-2; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: HIV-1 specific T cell response; TCR signaling; peptide counting