Decreased sensitivity to tumour-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice

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.

Lack of TNFR2 expression by CD4+ T cells exacerbates experimental colitis

“…Although the proliferative capacity of TNFR2 À/À and WT CD4 + T cells is comparable, a significant difference in the sensitivity to AICD was noticed. Intriguingly, in the initial characterization of the TNFR2 À/À mouse, an increased resistance to TNF-induced T-cell death was in fact reported [38].…”

Lipopolysaccharide-Induced Osteoclastogenesis from Mononuclear Precursors: A Mechanism for Osteolysis in Chronic Otitis

“…Additionally, bone marrow from knockout mice was also used in this study. Knockout mice were on a C57/BL6 background and possessed targeted deletions of either IL-6 (IL-6 −/− ; Kopf et al 1994), TNF receptor 1 (TNFR1 −/− ; Peschon et al 1998), TNF receptor 2 (TNFR2 −/− ; Erickson et al 1994), both TNF receptors 1 and 2 (TNFR1/2 −/− ; Peschon et al 1998), or IL-1 receptor 1 (IL-1R1 −/− ; Glaccum et al 1997). All mice were obtained from Jackson Laboratories (Bar Harbor, ME, USA).…”

Lymphoid abnormalities in CD40 ligand transgenic mice suggest the need for tight regulation in gene therapy approaches to hyper immunoglobulin M (IgM) syndrome

“…The TNF-␣, lymphotoxin ␣ (LT␣), and LT␤ genes and their receptors have been disrupted. [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] The results obtained demonstrate a previously unrealized role for these cytokines in peripheral lymphoid organ development. TNF-␣ Ϫ/Ϫ mice have expanded marginal zones in the spleen but are deficient in follicles and follicular dendritic cells, whereas LT␣ Ϫ/Ϫ mice show a more severe developmental defect, as they are missing peripheral lymph nodes and Peyer's patches (PP).…”

“…LT␤ Ϫ/Ϫ mice have a somewhat intermediate phenotype, as they lack peripheral lymph nodes, PP, primary and secondary follicles, and follicular dendritic cells, but have mesenteric and cervical lymph nodes. Mice lacking the p75 TNF receptor (TNFR) develop lymph nodes and PP, 25 whereas mice with interrupted p55 TNFR have been reported to have normal or absent PP. 32,38 Defective GC formation is also seen in mice after inactivation of nuclear factor-B2 and bcl-3 genes, which are also involved in TNFR signaling pathways.…”