Decreased sensitivity to tumour-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice.
Tumour necrosis factor (TNF) elicits multiple biological effects through two distinct cell surface receptors, TNF-R1 (p55) and TNF-R2 (p75). Most TNF-mediated biological responses, such as cell death, gene induction, antiviral activity and cytokine production, have been attributed to TNF-R1 (refs 1-5). Gene targeting of this receptor confirms its role in the lethality attributable to low doses of lipopolysaccharide after sensitization with D-galactosamine; surprisingly, the toxicity of high doses of lipopolysaccharide was unaffected. The function of TNF-R2 is less well understood, although there are data supporting a role in T-cell development and the proliferation of cytotoxic T lymphocytes. To clarify the physiological role of TNF-R2, we have generated mice deficient in this receptor by gene targeting. The TNF-R2-/- mice show normal T-cell development and activity, but we find that they have increased resistance to TNF-induced death. Additionally, such mice injected subcutaneously with TNF show a dramatic decrease in tissue necrosis, indicating that this receptor plays a role in the necrotic effects of TNF.
Erickson
S L
SL
Department of Cell Genetics, Genentech, South San Francisco, California 94080.
de Sauvage
F J
FJ
Kikly
K
K
Carver-Moore
K
K
Pitts-Meek
S
S
Gillett
N
N
Sheehan
K C
KC
Schreiber
R D
RD
Goeddel
D V
DV
Moore
M W
MW
D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology; D002454:Cell Differentiation / Q000502:physiology; D018390:Gene Targeting; D006801:Humans; D008088:Listeriosis / Q000276:immunology; D051379:Mice; D009336:Necrosis / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II; D012867:Skin / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha