DECREASED SENSITIVITY TO TUMOR-NECROSIS-FACTOR BUT NORMAL T-CELL DEVELOPMENT IN TNF RECEPTOR-2-DEFICIENT MICE

TUMOUR necrosis factor (TNF) elicits multiple biological effects throu gh two distinct cell surface receptors, TNF-R1 (p55) and TNF-R2 (p75). Most TNF-mediated biological responses, such as cell death, gene indu ction, antiviral activity and cytokine production, have been attribute d to TNF-R1 (refs 1-5). Gene targeting of this receptor confirms its r ole in the lethality attributable to low doses of lipopolysaccharide a fter sensitization with D-galactosamine(6,7); surprisingly, the toxici ty 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 lympho cytes(8,9). To clarify the physiological role of TNF-R2, we have gener ated mice deficient in this receptor by gene targeting. The TNF-R2(-/- ) mice show normal T-cell development and activity, but we find that t hey have increased resistance to TNF-induced death. Additionally, such mice injected subcutaneously with TNF show a dramatic decrease in tis sue necrosis, indicating that this receptor plays a role in the necrot ic effects of TNF.