On the role of the inhibitory receptor LAG-3 in acute and chronic LCMV infection

Int Immunol. 2010 Jan;22(1):13-23. doi: 10.1093/intimm/dxp107. Epub 2009 Oct 30.

Abstract

Chronic viral infections are often characterized by CD8 T-cell responses with poor cytokine secretion potential and limited expansion of the CD8 T-cell pool, collectively referred to as CD8 T-cell exhaustion. Exhaustion of lymphocytic choriomeningitis virus (LCMV)-specific CD8 T cells was shown to be partially regulated by the inhibitory receptor programmed death 1 (PD-1). Here, we demonstrate that exhausted LCMV-specific CD8 T cells also express the negative regulatory receptor lymphocyte activation gene 3 (LAG-3) which is mainly expressed on cells co-expressing the negative regulatory receptors PD-1 and Tim-3. Expression levels of LAG-3 on anti-viral CD8 T cells remain stable over short-term in vitro stimulations in presence of antigenic peptide. Nevertheless, in vitro and in vivo blockade of LAG-3 did not rescue cytokine production by virus-specific CD8 T cells and did not alter the virus titer in various organs. Likewise, chronic LCMV infection of LAG-3-/- mice led to a comparable degree of T-cell exhaustion as observed in C57BL/6 controls and to similar virus titers. Further, LAG-3 did not influence T-cell activation or cell division during chronic LCMV infection. These data suggest that even though LAG-3 is continuously up-regulated on LCMV-specific exhausted CD8 T cells, it alone does not significantly contribute to T-cell exhaustion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • Antigens, CD / metabolism*
  • Antigens, Surface / immunology
  • Antigens, Surface / metabolism
  • Apoptosis Regulatory Proteins / immunology
  • Apoptosis Regulatory Proteins / metabolism*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / virology
  • Cell Proliferation
  • Cells, Cultured
  • Hepatitis A Virus Cellular Receptor 2
  • Lymphocyte Activation / genetics
  • Lymphocytic Choriomeningitis / genetics
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic Choriomeningitis / pathology
  • Lymphocytic choriomeningitis virus / immunology*
  • Lymphocytic choriomeningitis virus / pathogenicity
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Programmed Cell Death 1 Receptor
  • Receptors, Virus / metabolism
  • Viral Load / genetics
  • Virulence

Substances

  • Antigens, CD
  • Antigens, Surface
  • Apoptosis Regulatory Proteins
  • CD223 antigen
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Virus