CD137-deficient mice have reduced NK/NKT cell numbers and function, are resistant to lipopolysaccharide-induced shock syndromes, and have lower IL-4 responses.
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.
Vinay
Dass S
DS
Louisiana State University Eye Center, Louisiana State University Health Sciences Center School of Medicine, New Orleans, LA 70112, USA.
Choi
Beom K
BK
Bae
Jun S
JS
Kim
Won Y
WY
Gebhardt
Bryan M
BM
Kwon
Byoung S
BS
D053330:4-1BB Ligand; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D015703:Antigens, CD; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000276:immunology / Q000473:pathology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D008070:Lipopolysaccharides / Q000633:toxicity*; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D012772:Shock, Septic / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013577:Syndrome; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology
D053330:4-1BB Ligand; D019138:Antibodies, Blocking; D015703:Antigens, CD; D008024:Ligands; D008070:Lipopolysaccharides; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; C505975:Tnfsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma