Negative regulation of T cell homeostasis by lymphocyte activation gene-3 (CD223)

J Immunol. 2005 Jan 15;174(2):688-95. doi: 10.4049/jimmunol.174.2.688.

Abstract

Lymphocyte homeostasis is a central biological process that is tightly regulated. However, its molecular and cellular control is poorly understood. We show that aged mice deficient in lymphocyte activation gene 3 (LAG-3), an MHC class II binding CD4 homologue, have twice as many T cells as wild-type controls. CD4(+) and CD8(+) LAG-3-deficient T cells showed enhanced homeostatic expansion in lymphopenic hosts, which was abrogated by ectopic expression of wild-type LAG-3, but not by a signaling-defective mutant. In addition, in vivo treatment with anti-LAG-3 mAb resulted in enhanced T cell expansion to a level comparable to that in LAG-3-deficient cells. This deregulation of T cell homeostasis also resulted in the expansion of multiple cell types, including B cells, macrophages, granulocytes, and dendritic cells. Lastly, regulatory T cells were dependent on LAG-3 for their optimal control of T cell homeostasis. Our data suggest that LAG-3 negatively regulates T cell homeostasis by regulatory T cell-dependent and independent mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aging / genetics
  • Aging / immunology
  • Amino Acid Motifs
  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • Antigens, CD / physiology*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / transplantation
  • Cell Differentiation / immunology
  • Cytoplasm / immunology
  • Down-Regulation / immunology*
  • Homeostasis / genetics
  • Homeostasis / immunology*
  • Injections, Intravenous
  • Lymphocyte Activation Gene 3 Protein
  • Lymphocyte Activation* / genetics
  • Lymphocyte Count
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Protein Structure, Tertiary
  • Receptors, Interleukin-2 / biosynthesis
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism*
  • T-Lymphocyte Subsets / transplantation

Substances

  • Antibodies, Monoclonal
  • Antigens, CD
  • Receptors, Interleukin-2
  • Lymphocyte Activation Gene 3 Protein
  • Lag3 protein, mouse