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

J Immunol. 2009 Jun 1;182(11):6659-69. doi: 10.4049/jimmunol.0804211.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigens / analysis
  • Antigens, CD / analysis
  • Antigens, CD / immunology*
  • Antigens, Differentiation / analysis
  • Antigens, Differentiation / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / transplantation
  • Cytokines
  • Immune Tolerance / immunology
  • Lymphocyte Activation / immunology*
  • Lymphocyte Activation Gene 3 Protein
  • Mice
  • Mice, Transgenic
  • Programmed Cell Death 1 Receptor
  • Signal Transduction / immunology


  • Antigens
  • Antigens, CD
  • Antigens, Differentiation
  • Cytokines
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Lymphocyte Activation Gene 3 Protein
  • Lag3 protein, mouse