title: TNF optimally activatives regulatory T cells by inducing TNF receptor superfamily members TNFR2, 4-1BB and OX40.
abstract: TNF is a pleiotropic cytokine with intriguing biphasic pro-inflammatory and anti-inflammatory effects. Our previous studies demonstrated that TNF up-regulated FoxP3 expression and activated and expanded CD4+ FoxP3+ regulatory T cells (Tregs) via TNFR2. Furthermore, TNFR2-expressing Tregs exhibited maximal suppressive activity. In this study, we show that TNF, in concert with IL-2, preferentially up-regulated mRNA and surface expression of TNFR2, 4-1BB and OX40 on Tregs. Agonistic antibodies against 4-1BB and OX40 also induced the proliferation of suppressive Tregs. Thus, TNF amplifies its stimulatory effect on Tregs by inducing TNF receptor superfamily (TNFRSF) members. In addition, administration of neutralizing anti-TNF Ab blocked LPS-induced expansion of splenic Tregs and up-regulation of TNFR2, OX40 and 4-1BB receptors on Tregs in vivo, indicating that the expansion of Tregs expressing these co-stimulatory TNFRSF members in response to LPS is mediated by TNF. Altogether, our novel data indicate that TNF preferentially up-regulates TNFR2 on Tregs, and this is amplified by the stimulation of 4-1BB and OX40, resulting in the optimal activation of Tregs and augmented attenuation of excessive inflammatory responses.
authors.affiliation: Laboratory of Molecular Immunoregulation, Cancer Inflammation Program, Center for Cancer Research, NCI-Frederick, Frederick, MD 21702-1201, USA.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Hamano
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Huang
authors.forename: Teizo
authors.initials: T
authors.lastname: Yoshimura
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Oppenheim
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
mesh_terms: D053330:4-1BB Ligand / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal; D005260:Female; D005434:Flow Cytometry; D007249:Inflammation; D007376:Interleukin-2 / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053262:Receptors, OX40 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000096:biosynthesis* / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000276:immunology*
chemical_list: D053330:4-1BB Ligand; D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D053262:Receptors, OX40; D047889:Receptors, Tumor Necrosis Factor, Type II; C505717:Tnfrsf4 protein, mouse; D048069:Tumor Necrosis Factors