O'Malley John T, Sehra Sarita, Thieu Vivian T, Yu Qing, Chang Hua-Chen, Stritesky Gretta L, Nguyen Evelyn T, Mathur Anubhav N, Levy David E, Kaplan Mark H
Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, IN 46202, USA.
Immunology. 2009 Aug;127(4):587-95. doi: 10.1111/j.1365-2567.2008.03037.x.
T-cell responses to a cytokine milieu instruct the development of multiple effector phenotypes. While transforming growth factor-beta(1) (TGF-beta(1)) inhibits the development of T helper type 1 (Th1) and Th2 cells, we demonstrate that like interleukin-6 (IL-6) and IL-4, IL-12 can inhibit the development of TGF-beta(1)-induced Foxp3-expressing adaptive T regulatory (aTreg) cells. Signal transducer and activator of transcription 4 (STAT4) is critical for the response to IL-12, although there is a parallel pathway involving T box expressed in T cells (T-bet), and cells from mice double-deficient in STAT4 and T-bet are refractory to the inhibition of aTreg-cell development by IL-12. While the ability of these cytokines to promote Th differentiation may contribute to this effect, we observe that culture with IL-12, or other instructive cytokines, results in an increase in repressive chromatin modifications at the Foxp3 locus that limit STAT5 binding to Foxp3, without observed effects on IL-2 signalling pathways. In a model of allergic lung inflammation there are increased percentages of Treg cells in the lungs of Stat4(-/-) mice, compared with wild-type mice, and increases in Treg cells correlate with decreased allergic inflammation. Overall, these results suggest an important role for STAT4 in regulating Treg-cell development.
T细胞对细胞因子环境的反应指导了多种效应器表型的发育。虽然转化生长因子-β(1)（TGF-β(1)）抑制辅助性T细胞1型（Th1）和Th2细胞的发育，但我们证明，与白细胞介素-6（IL-6）和IL-4一样，IL-12可以抑制TGF-β(1)诱导的表达Foxp3的适应性调节性T细胞（aTreg）的发育。信号转导和转录激活因子4（STAT4）对于对IL-12的反应至关重要，尽管存在一条涉及T细胞中表达的T盒（T-bet）的平行途径，并且来自STAT4和T-bet双缺陷小鼠的细胞对IL-12抑制aTreg细胞发育具有抗性。虽然这些细胞因子促进Th分化的能力可能有助于产生这种效应，但我们观察到，用IL-12或其他指导性细胞因子培养会导致Foxp3基因座处抑制性染色质修饰增加，从而限制STAT5与Foxp3的结合，而未观察到对IL-2信号通路的影响。在过敏性肺部炎症模型中，与野生型小鼠相比，Stat4(-/-)小鼠肺部的Treg细胞百分比增加，并且Treg细胞的增加与过敏性炎症的减轻相关。总体而言，这些结果表明STAT4在调节Treg细胞发育中起重要作用。
