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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3383-3392
Number of pages10
JournalJournal of Clinical Investigation
Volume117
Issue number11
DOIs
StatePublished - Nov 1 2007

ASJC Scopus subject areas

  • Medicine(all)

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    Grosso, J. F., Kelleher, C. C., Harris, T. J., Maris, C. H., Hipkiss, E. L., De Marzo, A., Anders, R., Netto, G., Getnet, D., Bruno, T. C., Goldberg, M. V., Pardoll, D. M., & Drake, C. G. (2007). LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. Journal of Clinical Investigation, 117(11), 3383-3392. https://doi.org/10.1172/JCI31184