Nitric oxide induces CD4+CD25+ Foxp3- regulatory T cells from CD4+CD25- T cells via p53, IL-2, and OX40
Nitric oxide induces CD4+CD25+ Foxp3- regulatory T cells from CD4+CD25- T cells via p53, IL-2, and OX40
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DOI：
10.1073/pnas.0703725104
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发表时间：
2007-09-25
影响因子：
11.1
通讯作者：
Liew, Foo Y.
中科院分区：
文献类型：
--
作者：
Niedbala, Wanda;Cai, Beilei;Liew, Foo Y.
免疫系统的主要目标是在防御病原体和避免自身免疫性疾病之间建立平衡。这种平衡部分是通过调节性T细胞(Treg)实现的。CD4(+)CD25(+)Tregs是自然产生的或由抗原诱导产生的，其特征是表达X连锁的叉头/翼状螺旋转录因子Foxp3。在这里，我们报告了一个以前未被识别的亚群，来自于一氧化氮(NO)诱导的CD4(+)CD25(-)T细胞。Tregs(NO-Tregs)的诱导不依赖于cGMP，但依赖于P53、IL-2和OX40。NO-Tregs产生IL-4和IL-10，但不产生IL-2、干扰素-γ或转化生长因子β。这些细胞是GITR(+)、CD27(+)、T-bet(低)、GATA3(高)和Foxp3(-)。在体外，NO-Tregs抑制CD4+CD25-T细胞的增殖；在体内，NO-Tregs以IL-10依赖的方式减轻结肠炎和胶原诱导的关节炎。在LIPs和干扰素-γ的存在下，过继转移CD_4+CD_(25)-T细胞的SCID小鼠体内也能诱导产生NO-Tregs，这种诱导作用可被PAN-NO合酶抑制剂N-G-单甲基-L-精氨酸完全抑制。因此，我们的发现揭示了NO通过NO-P53-IL-2-OX40-Survivin信号通路参与T细胞分化和发育的先前未知的功能。
The principal aim of the immune system is to establish a balance between defense against pathogens and avoidance of autoimmune disease. This balance is achieved partly through regulatory T cells (Tregs). CD4(+)CD25(+) Tregs are either naturally occurring or induced by antigens and are characterized by the expression of the X-linked forkhead/winged helix transcription factor, Foxp3. Here we report a previously unrecognized subset of CD4+CD25+ Tregs derived from CD4(+)CD25(-) Tcells induced by nitric oxide (NO). The induction of Tregs (NO-Tregs) is independent of cGMP but depends on p53, IL-2, and OX40. NO-Tregs produced IL-4 and IL-10, but not IL-2, IFN gamma, or TGF beta. The cells were GITR(+), CD27(+), T-bet(low), GATA3(high), and Foxp3(-). NO-Tregs suppressed the proliferation of CD4+CD25- T cells in vitro and attenuated colitis- and collagen-induced arthritis in vivo in an IL-10-dependent manner. NO-Tregs also were induced in vivo in SCID mice adoptively transferred with CD4+CD25- T cells in the presence of LIPS and IFN gamma, and the induction was completely inhibited by N-G-monomethyl-L-argi nine, a pan NO synthase inhibitor. Therefore, our findings uncovered a previously unrecognized function of NO via the NO-p53-IL-2-OX40-survivin signaling pathway for T cell differentiation and development.