Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells

Joseph F. Grosso, Monica V. Goldberg, Derese Getnet, Tullia C. Bruno, Hung Rong Yen, Kristin J. Pyle, Edward Hipkiss, Dario A.A. Vignali, Drew M. Pardoll, Charles G. Drake

Research output: Contribution to journalArticlepeer-review

157 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)6659-6669
Number of pages11
JournalJournal of Immunology
Volume182
Issue number11
DOIs
StatePublished - Jun 1 2009

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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