Laboratory of Molecular Immunoregulation, Cancer Inflammation Program, Center for Cancer Research, NCI-Frederick, Frederick, MD 21702-1201, USA.
Eur J Immunol. 2011 Jul;41(7):2010-20. doi: 10.1002/eji.201041205.
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.
肿瘤坏死因子（TNF）是一种具有复杂双重促炎和抗炎作用的多效细胞因子。我们之前的研究表明，TNF 通过 TNFR2 上调 FoxP3 表达并激活和扩增 CD4+FoxP3+调节性 T 细胞（Treg）。此外，表达 TNFR2 的 Treg 表现出最大的抑制活性。在这项研究中，我们表明 TNF 与 IL-2 一起优先上调 Treg 上 TNFR2、4-1BB 和 OX40 的 mRNA 和表面表达。针对 4-1BB 和 OX40 的激动性抗体也诱导了抑制性 Treg 的增殖。因此，TNF 通过诱导 TNF 受体超家族（TNFRSF）成员来放大其对 Treg 的刺激作用。此外，给予中和抗 TNF Ab 可阻断 LPS 诱导的脾 Treg 扩增以及体内 Treg 上 TNFR2、OX40 和 4-1BB 受体的上调，表明对 LPS 作出反应的表达这些共刺激性 TNFRSF 成员的 Treg 的扩增是由 TNF 介导的。总之，我们的新数据表明，TNF 优先上调 Treg 上的 TNFR2，并且通过 4-1BB 和 OX40 的刺激得到放大，从而导致 Treg 的最佳激活和过度炎症反应的增强衰减。
