title: LAG-3 Confers a Competitive Disadvantage upon Antiviral CD8+ T Cell Responses.
abstract: Ongoing clinical trials are evaluating the benefits of systemic blockade of lymphocyte activation gene-3 (LAG-3) signals to improve immunity to tumors. Those studies are founded on the well-established inhibitory role of LAG-3 in regulating CD8(+) T cells during chronic virus infection and antitumor responses. However, the T cell response in LAG-3-deficient mice is similar in size and function to that in wild type animals, suggesting LAG-3 has nuanced immune-regulatory functions. We performed a series of adoptive transfer experiments in mice to better understand the T cell-intrinsic functions of LAG-3 in the regulation of CD8(+) T cell responses. Our results indicate that LAG-3 expression by CD8(+) T cells inhibits their competitive fitness and results in a slightly reduced rate of cell division in comparison with LAG-3-deficient cells. This cell-intrinsic effect of LAG-3 was consistent across both acute and chronic virus infections. These data show that LAG-3 directly modulates the size of the T cell response and support the use of LAG-3 blockade regimens to enhance CD8(+) T cell responses.
authors.affiliation: Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC 27599; and.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Cook
authors.affiliation: Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC 27599; and Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599 jwhitmir@email.unc.edu.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Whitmire
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D049109:Cell Proliferation; D002478:Cells, Cultured; D006023:Glycoproteins / Q000276:immunology; D007111:Immunity, Cellular; D008213:Lymphocyte Activation; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D000956:Antigens, Viral; D006023:Glycoproteins; D010446:Peptide Fragments; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus; D000093322:Lymphocyte Activation Gene 3 Protein