title: LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems.
abstract: Lymphocyte activation gene-3 (LAG-3) is a cell-surface molecule with diverse biologic effects on T cell function. We recently showed that LAG-3 signaling is important in CD4+ regulatory T cell suppression of autoimmune responses. Here, we demonstrate that LAG-3 maintains tolerance to self and tumor antigens via direct effects on CD8+ T cells using 2 murine systems. Naive CD8+ T cells express low levels of LAG-3, and expression increases upon antigen stimulation. Our data show increased levels of LAG-3 protein on antigen-specific CD8+ T cells within antigen-expressing organs or tumors. In vivo antibody blockade of LAG-3 or genetic ablation of the Lag-3 gene resulted in increased accumulation and effector function of antigen-specific CD8+ T cells within organs and tumors that express their cognate antigen. Most notably, combining LAG-3 blockade with specific antitumor vaccination resulted in a significant increase in activated CD8+ T cells in the tumor and disruption of the tumor parenchyma. A major component of this effect was CD4 independent and required LAG-3 expression by CD8+ T cells. Taken together, these data demonstrate a direct role for LAG-3 on CD8+ T cells and suggest that LAG-3 blockade may be a potential cancer treatment.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center and Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Grosso
authors.forename: Cristin C
authors.initials: CC
authors.lastname: Kelleher
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Harris
authors.forename: Charles H
authors.initials: CH
authors.lastname: Maris
authors.forename: Edward L
authors.initials: EL
authors.lastname: Hipkiss
authors.forename: Angelo
authors.initials: A
authors.lastname: De Marzo
authors.forename: Robert
authors.initials: R
authors.lastname: Anders
authors.forename: George
authors.initials: G
authors.lastname: Netto
authors.forename: Derese
authors.initials: D
authors.lastname: Getnet
authors.forename: Tullia C
authors.initials: TC
authors.lastname: Bruno
authors.forename: Monica V
authors.initials: MV
authors.lastname: Goldberg
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; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002460:Cell Line; D049109:Cell Proliferation; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017634:Self Tolerance / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D000093322:Lymphocyte Activation Gene 3 Protein