LAG-3 Confers a Competitive Disadvantage upon Antiviral CD8+ T Cell Responses

J Immunol. 2016 Jul 1;197(1):119-27. doi: 10.4049/jimmunol.1401594. Epub 2016 May 20.

Abstract

Ongoing clinical trials are evaluating the benefits of systemic blockade of lymphocyte activation gene-3 (LAG-3) signals to improve immunity to tumors. Those studies are founded on the well-established inhibitory role of LAG-3 in regulating CD8(+) T cells during chronic virus infection and antitumor responses. However, the T cell response in LAG-3-deficient mice is similar in size and function to that in wild type animals, suggesting LAG-3 has nuanced immune-regulatory functions. We performed a series of adoptive transfer experiments in mice to better understand the T cell-intrinsic functions of LAG-3 in the regulation of CD8(+) T cell responses. Our results indicate that LAG-3 expression by CD8(+) T cells inhibits their competitive fitness and results in a slightly reduced rate of cell division in comparison with LAG-3-deficient cells. This cell-intrinsic effect of LAG-3 was consistent across both acute and chronic virus infections. These data show that LAG-3 directly modulates the size of the T cell response and support the use of LAG-3 blockade regimens to enhance CD8(+) T cell responses.

Publication types

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

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Antigens, Viral / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / virology
  • Cell Proliferation*
  • Cells, Cultured
  • Glycoproteins / immunology
  • Immunity, Cellular
  • Lymphocyte Activation
  • Lymphocyte Activation Gene 3 Protein
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic choriomeningitis virus / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Peptide Fragments / immunology
  • Viral Proteins / immunology

Substances

  • Antigens, CD
  • Antigens, Viral
  • Glycoproteins
  • Peptide Fragments
  • Viral Proteins
  • glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus
  • Lymphocyte Activation Gene 3 Protein