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Immunol Cell Biol. 2010 Jul;88(5):586-95. doi: 10.1038/icb.2010.12. Epub 2010 Mar 9.

TNFRI is a positive T-cell costimulatory molecule important for the timing of cytokine responses.

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Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece.


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.

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