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Decreased sensitivity to tumour-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice
S L Erickson1, F J de Sauvage, K Kikly
1Department of Cell Genetics, Genentech, South San Francisco, California 94080.
Abstract:
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.
Insights
Tumour necrosis factor receptor 2 (TNF-R2) plays a key role in mediating TNF-induced tissue necrosis. Mice lacking TNF-R2 exhibit resistance to TNF-induced death and reduced necrosis, clarifying TNF-R2
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Tumour necrosis factor (TNF) exerts biological effects via TNF-R1 and TNF-R2 receptors.
- TNF-R1 mediates most known TNF responses, including cell death and cytokine production.
- The specific role of TNF-R2 remains less understood, with some evidence suggesting involvement in T-cell functions.
Purpose of the Study:
- To elucidate the physiological function of TNF-R2.
- To investigate the role of TNF-R2 in TNF-mediated biological responses, particularly cell death and tissue necrosis.
Main Methods:
- Generation of gene-targeted mice deficient in TNF-R2 (TNF-R2-/-).
- Assessment of T-cell development and activity in TNF-R2-/- mice.
- Evaluation of TNF-induced death and tissue necrosis in TNF-R2-/- mice following TNF administration.
Main Results:
- TNF-R2-/- mice displayed normal T-cell development and activity.
- These mice showed increased resistance to TNF-induced death.
- Subcutaneous TNF injection in TNF-R2-/- mice resulted in significantly reduced tissue necrosis.
Conclusions:
- TNF-R2 is crucial for mediating TNF-induced tissue necrosis.
- TNF-R2 contributes to TNF-induced lethality and inflammatory responses.
- These findings highlight distinct roles for TNF-R1 and TNF-R2 in TNF signaling pathways.