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LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems
Joseph F. Grosso, … , Drew M. Pardoll, Charles G. Drake
Joseph F. Grosso, … , Drew M. Pardoll, Charles G. Drake
Published October 11, 2007
Citation Information: J Clin Invest. 2007;117(11):3383-3392. https://doi.org/10.1172/JCI31184.
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Research Article Oncology Article has an altmetric score of 30

LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems

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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

Joseph F. Grosso, Cristin C. Kelleher, Timothy J. Harris, Charles H. Maris, Edward L. Hipkiss, Angelo De Marzo, Robert Anders, George Netto, Derese Getnet, Tullia C. Bruno, Monica V. Goldberg, Drew M. Pardoll, Charles G. Drake

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Figure 1

LAG-3 blockade enhances the accumulation of HA-specific CD8+ cells in a model of self tolerance.

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LAG-3 blockade enhances the accumulation of HA-specific CD8+ cells in a ...
We transferred 106 LAG-3+/+ or LAG-3–/–CD8+Thy1.1+ clone 4 CD8+ cells into Thy1.2+C3-HAhigh mice. Mice receiving antibody were given 0.2 mg αLAG-3 i.p. at the time of transfer and 3 days later. At indicated time points after transfer, single-cell suspensions were made from lungs and analyzed for LAG-3 expression and function. (A) CD8+ and Thy1.1+ were gated to determine expression of LAG-3 on CD8+ T cells taken directly from lungs of C3-HA mice. Both surface expression (left) and intracellular staining (middle and right) were performed for LAG-3 expression. Endogenous (endo) CD8 populations within lungs were also assessed. Blue lines, LAG-3; red lines, rat IgG1 isotype; black lines, LAG-3–/– cells. Max, maximum. (B) Lungs from C3-HA mice were analyzed 7 days after transfer for percentage of CD8+Thy1.1+ cells by staining for Thy1.1 (C). Clonotypic cells from B were analyzed for division by dilution of CFSE and IFN-γ production by intracellular staining after stimulation in vitro in the presence of HA peptide plus monensin for 5 hours. SSC-H, side scatter. (D and E) Absolute numbers of clonotypic and IFN-γ+ clonotypic cells/lung after αLAG-3 treatment or transfer of LAG-3–/– clone 4 cells. The mean from 3 mice per group is shown. Each experiment was performed 3 times with data from 1 representative experiment shown.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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