title: Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells.
abstract: Lymphocyte Activation Gene-3 (LAG-3) is a transmembrane protein that binds MHC class II, enhances regulatory T cell activity, and negatively regulates cellular proliferation, activation, and homeostasis of T cells. Programmed Death 1 (PD-1) also negatively regulates T cell function. LAG-3 and PD-1 are both transiently expressed on CD8 T cells that have been stimulated during acute activation. However, both LAG-3 and PD-1 remain on CD8 T cells at high levels after stimulation within tolerizing environments. Our previous data demonstrated that blockade of either LAG-3 or PD-1 using mAb therapy in combination with vaccination restores the function of tolerized Ag-specific CD8 T cells in models of self and tumor tolerance. It is unclear whether tolerized CD8 T cells coexpress PD-1 and LAG-3 or whether PD-1 and LAG-3 mark functionally distinct populations of CD8 T cells. In this study, we describe three populations of CD8 T cells activated under tolerizing conditions based on LAG-3 and PD-1 staining, each with distinct phenotypic and functional characteristics. From a mechanistic perspective, both Ag concentration and proinflammatory signals control the expression of LAG-3 and PD-1 phenotypes on CD8 T cells under activating and tolerizing conditions. These results imply that signaling through the PD-1 and LAG-3 pathways have distinct functional consequences to CD8 T cells under tolerizing conditions and manipulation of both Ag and cytokine signaling can influence CD8 tolerance through LAG-3 and PD-1.
authors.affiliation: Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Grosso
authors.forename: Monica V
authors.initials: MV
authors.lastname: Goldberg
authors.forename: Derese
authors.initials: D
authors.lastname: Getnet
authors.forename: Tullia C
authors.initials: TC
authors.lastname: Bruno
authors.forename: Hung-Rong
authors.initials: HR
authors.lastname: Yen
authors.forename: Kristin J
authors.initials: KJ
authors.lastname: Pyle
authors.forename: Edward
authors.initials: E
authors.lastname: Hipkiss
authors.forename: Dario A A
authors.initials: DA
authors.lastname: Vignali
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.forename: Charles G
authors.initials: CG
authors.lastname: Drake
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens / Q000032:analysis; D015703:Antigens, CD / Q000032:analysis / Q000276:immunology*; D000943:Antigens, Differentiation / Q000032:analysis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D016207:Cytokines; D007108:Immune Tolerance / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000276:immunology; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D000941:Antigens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D016207:Cytokines; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D000093322:Lymphocyte Activation Gene 3 Protein; C000720327:Lag3 protein, mouse