title: TNFRI is a positive T-cell costimulatory molecule important for the timing of cytokine responses.
abstract: Tumor necrosis factor (TNF)- and TNF receptor I (TNFRI)-deficient mice are resistant to initiation and show delayed resolution of disease in paradigms of autoimmune disease, but the contribution of TNF/TNFRI signaling to T-cell activation and effector responses has not been determined. In this study, we investigated the role of TNFRI in T-cell receptor (TCR)-mediated T-cell activation in vitro and in vivo using CD3(+)-enriched primary T cells and mice deficient in TNFRI. Following TCR engagement, TNFRI knockout (KO) T cells showed significantly delayed proliferation, cell division, upregulation of interleukin 2 (IL-2) and IL-2 receptor alpha chain (CD25) mRNA and cell-surface expression of CD25 compared with wild-type (WT) cells. Thus, WT and TNFRI KO cells showed equivalent proliferation peaks at 48 and 72 h, respectively. TNFRI KO mice also developed a defective primary T-cell response to ovalbumin and an acute contact hypersensitivity response to oxazolone (4-ethoxymethylene-2-phenyl-2-oxazolin-5-one). However, TNFRI KO splenocytes that were stimulated by TCR engagement in vitro for 96 h produced significantly higher intracellular levels of interferon-gamma (IFN-gamma), IL-2 and TNF-alpha, but not IL-17, compared with WT cells, in correlation with their relatively higher proliferation rate at this time point. Further, TCR-stimulated CD3(+)-enriched TNFRI KO T cells showed similarly higher production and secretion of IFN-gamma and IL-2 compared with WT, suggesting that TNFRI-mediated cytokine regulation might involve a T-cell autonomous effect. Our results show a novel role for TNFRI as a positive T-cell costimulatory molecule that is important for timely T-cell activation and effector cytokine production and the development of primary immune responses in mice.
authors.affiliation: Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Evangelidou
authors.forename: Vivian
authors.initials: V
authors.lastname: Tseveleki
authors.forename: Sotiris-Spyros
authors.initials: SS
authors.lastname: Vamvakas
authors.forename: Lesley
authors.initials: L
authors.lastname: Probert
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D005434:Flow Cytometry; D047468:Immunoprecipitation; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013995:Time
chemical_list: D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D047888:Receptors, Tumor Necrosis Factor, Type I