TNF optimally activatives regulatory T cells by inducing TNF receptor superfamily members TNFR2, 4-1BB and OX40

Ryoko Hamano, Jiaqiang Huang, Teizo Yoshimura, Joost J. Oppenheim, Xin Chen

Research output: Contribution to journalArticle

48 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2010-2020
Number of pages11
JournalEuropean Journal of Immunology
Volume41
Issue number7
DOIs
Publication statusPublished - Jul 2011
Externally publishedYes

Fingerprint

Receptors, Tumor Necrosis Factor, Type II
Tumor Necrosis Factor Receptors
Regulatory T-Lymphocytes
CD137 Antigens
Up-Regulation
Interleukin-2
Anti-Inflammatory Agents
Cytokines
Messenger RNA
Antibodies

Keywords

  • Co-stimulation
  • Immune regulation
  • TNF
  • Tregs

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

TNF optimally activatives regulatory T cells by inducing TNF receptor superfamily members TNFR2, 4-1BB and OX40. / Hamano, Ryoko; Huang, Jiaqiang; Yoshimura, Teizo; Oppenheim, Joost J.; Chen, Xin.

In: European Journal of Immunology, Vol. 41, No. 7, 07.2011, p. 2010-2020.

Research output: Contribution to journalArticle

Hamano, Ryoko ; Huang, Jiaqiang ; Yoshimura, Teizo ; Oppenheim, Joost J. ; Chen, Xin. / TNF optimally activatives regulatory T cells by inducing TNF receptor superfamily members TNFR2, 4-1BB and OX40. In: European Journal of Immunology. 2011 ; Vol. 41, No. 7. pp. 2010-2020.
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