CD137-deficient mice have reduced NK/NKT cell numbers and function, are resistant to lipopolysaccharide-induced shock syndromes, and have lower IL-4 responses

J Immunol. 2004 Sep 15;173(6):4218-29. doi: 10.4049/jimmunol.173.6.4218.

Abstract

CD137, a member of the TNF superfamily, is involved in T cell and NK cell activation and cytokine production. To establish its in vivo role in systems dependent on NK and NKT cells, we studied the response of CD137-/- mice to LPS-induced shock, tumor killing, and their IL-4-controlled Th2 responses. In both high and low dose shock models, all the CD137-deficient mice, but none of the wild-type BALB/c mice, survived. After injection of LPS/2-amino-2-deoxy-D-galactose (D-gal), CD137-/- mice had reduced serum cytokine levels and substantially impaired liver IFN-gamma and TNF-alpha mRNA levels. Phenotypic analysis of mononuclear cells revealed fewer NK and NKT cells in the CD137-/- mice. The knockout mice did not generate a rapid IL-4 response after systemic T cell activation, or effective Ag-specific Th2 responses. In addition, both in vitro and in vivo NK-specific cytolytic activities were reduced. These findings suggest that CD137-directed NK/NKT cells play an important role in the inflammatory response leading to the production of proinflammatory cytokines, LPS-induced septic shock, and tumor killing, as well as IL-4-dependent Th2 responses.

Publication types

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

MeSH terms

  • 4-1BB Ligand
  • Animals
  • Antibodies, Blocking / pharmacology
  • Antigens, CD
  • Cell Line, Tumor
  • Cells, Cultured
  • Chemical and Drug Induced Liver Injury / genetics
  • Chemical and Drug Induced Liver Injury / immunology
  • Chemical and Drug Induced Liver Injury / pathology
  • Cytotoxicity, Immunologic / genetics
  • Immunity, Innate / genetics
  • Interferon-gamma / antagonists & inhibitors
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / genetics
  • Interleukin-4 / antagonists & inhibitors
  • Interleukin-4 / metabolism
  • Interleukin-4 / physiology*
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Killer Cells, Natural / pathology
  • Ligands
  • Lipopolysaccharides / toxicity*
  • Lymphocyte Count
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Nerve Growth Factor / antagonists & inhibitors
  • Receptors, Nerve Growth Factor / deficiency*
  • Receptors, Nerve Growth Factor / genetics*
  • Receptors, Nerve Growth Factor / physiology
  • Receptors, Tumor Necrosis Factor / antagonists & inhibitors
  • Receptors, Tumor Necrosis Factor / deficiency*
  • Receptors, Tumor Necrosis Factor / genetics*
  • Receptors, Tumor Necrosis Factor / physiology
  • Shock, Septic / genetics*
  • Shock, Septic / immunology*
  • Shock, Septic / pathology
  • Shock, Septic / prevention & control
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Syndrome
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocyte Subsets / pathology
  • Th2 Cells / immunology
  • Th2 Cells / metabolism
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / physiology

Substances

  • 4-1BB Ligand
  • Antibodies, Blocking
  • Antigens, CD
  • Ligands
  • Lipopolysaccharides
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf9 protein, mouse
  • Tnfsf9 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Tumor Necrosis Factor-alpha
  • Interleukin-4
  • Interferon-gamma