Chapoval Svetlana P, Dasgupta Preeta, Smith Elizabeth P, DeTolla Louis J, Lipsky Michael M, Kelly-Welch Ann E, Keegan Achsah D
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
J Immunol. 2011 Feb 15;186(4):2571-83. doi: 10.4049/jimmunol.1002567. Epub 2011 Jan 17.
Th2 cells induce asthma through the secretion of cytokines. Two such cytokines, IL-4 and IL-13, are critical mediators of many features of this disease. They both share a common receptor subunit, IL-4Rα, and signal through the STAT6 pathway. STAT6(-/-) mice have impaired Th2 differentiation and reduced airway response to allergen. Transferred Th2 cells were not able to elicit eosinophilia in response to OVA in STAT6(-/-) mice. To clarify the role of STAT6 in allergic airway inflammation, we generated mouse bone marrow (BM) chimeras. We observed little to no eosinophilia in OVA-treated STAT6(-/-) mice even when STAT6(+/+) BM or Th2 cells were provided. However, when Th2 cells were transferred to STAT6×Rag2(-/-) mice, we observed an eosinophilic response to OVA. Nevertheless, the expression of STAT6 on either BM-derived cells or lung resident cells enhanced the severity of OVA-induced eosinophilia. Moreover, when both the BM donor and recipient lacked lymphocytes, transferred Th2 cells were sufficient to induce the level of eosinophilia comparable with that of wild-type (WT) mice. The expression of STAT6 in BM-derived cells was more critical for the enhanced eosinophilic response. Furthermore, we found a significantly higher number of CD4(+)CD25(+)Foxp3(+) T cells (regulatory T cells [Tregs]) in PBS- and OVA-treated STAT6(-/-) mouse lungs compared with that in WT animals suggesting that STAT6 limits both naturally occurring and Ag-induced Tregs. Tregs obtained from either WT or STAT6(-/-) mice were equally efficient in suppressing CD4(+) T cell proliferation in vitro. Taken together, our studies demonstrate multiple STAT6-dependent and -independent features of allergic inflammation, which may impact treatments targeting STAT6.
Th2细胞通过分泌细胞因子诱导哮喘。其中两种细胞因子，即白细胞介素-4（IL-4）和白细胞介素-13（IL-13），是该疾病许多特征的关键介质。它们都共享一个共同的受体亚基IL-4Rα，并通过信号转导和转录激活因子6（STAT6）途径进行信号传导。STAT6基因敲除（-/-）小鼠的Th2分化受损，对变应原的气道反应降低。在STAT6（-/-）小鼠中，转移的Th2细胞无法引发针对卵清蛋白（OVA）的嗜酸性粒细胞增多。为了阐明STAT6在过敏性气道炎症中的作用，我们构建了小鼠骨髓（BM）嵌合体。我们观察到，即使提供了STAT6（+/+）骨髓或Th2细胞，经OVA处理的STAT6（-/-）小鼠中几乎没有嗜酸性粒细胞增多。然而，当将Th2细胞转移到STAT6×重组激活基因2（Rag2）基因敲除（-/-）小鼠中时，我们观察到对OVA的嗜酸性粒细胞反应。尽管如此，BM来源细胞或肺驻留细胞上STAT6的表达增强了OVA诱导的嗜酸性粒细胞增多的严重程度。此外，当BM供体和受体都缺乏淋巴细胞时，转移的Th2细胞足以诱导与野生型（WT）小鼠相当的嗜酸性粒细胞增多水平。BM来源细胞中STAT6的表达对增强的嗜酸性粒细胞反应更为关键。此外，我们发现，与WT动物相比，在经磷酸盐缓冲盐水（PBS）和OVA处理的STAT6（-/-）小鼠肺中CD4（+）CD25（+）叉头框蛋白3（Foxp3）+ T细胞（调节性T细胞[Tregs]）的数量明显更多，这表明STAT6限制天然存在的和抗原诱导的Tregs。从WT或STAT6（-/-）小鼠获得的Tregs在体外抑制CD4（+）T细胞增殖方面同样有效。综上所述，我们的研究证明了过敏性炎症的多种STAT6依赖性和非依赖性特征，这可能会影响针对STAT6的治疗。
