Niedbala Wanda, Cai Beilei, Liu Haiying, Pitman Nick, Chang Lynda, Liew Foo Y
Division of Immunology, Infection, and Inflammation, Glasgow Biomedical Research Centre, 120 University Place, University of Glasgow, Glasgow G12 8TA, United Kingdom.
Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15478-83. doi: 10.1073/pnas.0703725104. Epub 2007 Sep 17.
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(-) T cells 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, IFNgamma, or TGFbeta. 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 LPS and IFNgamma, and the induction was completely inhibited by N(G)-monomethyl-L-arginine, 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.
免疫系统的主要目标是在抵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（Tregs）实现的。CD4(+)CD25(+) Tregs要么是天然存在的，要么是由抗原诱导产生的，其特征是表达X连锁的叉头/翼状螺旋转录因子Foxp3。在此，我们报告了一种先前未被认识的CD4(+)CD25(+) Tregs亚群，它源自一氧化氮（NO）诱导的CD4(+)CD25(-) T细胞。Tregs（NO-Tregs）的诱导不依赖于环鸟苷酸（cGMP），但依赖于p53、白细胞介素-2（IL-2）和OX40。NO-Tregs产生IL-4和IL-10，但不产生IL-2、干扰素γ（IFNγ）或转化生长因子β（TGFβ）。这些细胞为糖皮质激素诱导的肿瘤坏死因子受体（GITR）阳性、CD27阳性、T盒转录因子（T-bet）低表达、GATA结合蛋白3（GATA3）高表达且Foxp3阴性。NO-Tregs在体外抑制CD4(+)CD25(-) T细胞的增殖，并以IL-10依赖的方式在体内减轻结肠炎和胶原诱导的关节炎。在存在脂多糖（LPS）和IFNγ的情况下，将CD4(+)CD25(-) T细胞过继转移到重症联合免疫缺陷（SCID）小鼠体内，也能在体内诱导出NO-Tregs，并且这种诱导被泛NO合酶抑制剂N(G)-单甲基-L-精氨酸完全抑制。因此，我们的研究结果揭示了NO通过NO-p53-IL-2-OX40-生存素信号通路在T细胞分化和发育方面的一种先前未被认识的功能。
