Overlapping and distinct roles of STAT4 and T-bet in the regulation of T cell differentiation and allergic airway inflammation
Overlapping and distinct roles of STAT4 and T-bet in the regulation of T cell differentiation and allergic airway inflammation
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DOI：
10.4049/jimmunol.180.10.6656
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发表时间：
2008-05-15
影响因子：
4.4
通讯作者：
Nakajima, Hiroshi
中科院分区：
文献类型：
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作者：
Furuta, Shunsuke;Kagami, Shin-ichiro;Nakajima, Hiroshi
T-bet和STAT 4在辅助性T细胞分化中起关键作用，特别是对于Th 1细胞。然而，T-bet和STAT 4在Th 1分化中的相对重要性和冗余性仍然未知。T-bet和STAT 4在过敏性气道炎症调节中的独立作用也是未知的。在这项研究中，我们通过比较T-bet缺陷（T-bet（-/-））小鼠，STAT 4（-/-）小鼠，以及T-bet和STAT 4双缺陷（T-bet（-/-）STAT 4（-/-））小鼠在相同的遗传背景下解决了这些问题。与野生型小鼠相比，T-bet（-/-）小鼠和STAT 4（-/-）小鼠的Th 1分化严重降低，但在T-bet（-/-）小鼠和STAT 4（-/-）小鼠中仍观察到Th 1分化。而在T-bet（-/-）STAT 4（-/-）小鼠中几乎未检测到Th 1细胞。相比之下，T-bet（-/-）小鼠中Th 17细胞的维持增强，但STAT 4（-/-）小鼠和T-bet（-/-）STAT 4（-/-）小鼠中Th 17细胞的维持减少。在体内，Ag诱导的嗜酸性粒细胞和中性粒细胞向气道的募集在T-bet（-/-）小鼠中增强，但在STAT 4（-/-）小鼠和T-bet（-/-）STAT 4（-/-）小鼠中减弱。在STAT 4（-/-）小鼠和T-bet（-/-）STAT 4（-/-）小鼠中，气道中Ag诱导的IL-17产生也减少。这些结果表明，STAT 4不仅在T-bet非依赖性Th 1分化中发挥不可或缺的作用，而且还参与维持Th 17细胞和增强过敏性气道炎症。
T-bet and STAT4 play critical roles in helper T cell differentiation, especially for Th1 cells. However, it is still unknown about the relative importance and redundancy of T-bet and STAT4 for Th1 differentiation. It is also unknown about their independent role of T-bet and STAT4 in the regulation of allergic airway inflammation. In this study, we addressed these issues by comparing T-bet-deficient (T-bet(-/-)) mice, STAT4(-/-) mice, and T-bet- and STAT4-double-deficient (T-bet(-/-)STAT4(-/-)) mice on the same genetic background. Th1 differentiation was severely decreased in T-bet(-/-) mice and STAT4(-/-) mice as compared with that in wild-type mice, but Th1 differentiation was still observed in T-bet(-/-) mice and STAT4(-/-) mice. However, Th1 cells were hardly detected in T-bet(-/-)STAT4(-/-) mice. In contrast, the maintenance of Th17 cells was enhanced in T-bet(-/-) mice but was reduced in STAT4(-/-) mice and T-bet(-/-)STAT4(-/-) mice. In vivo, Ag-induced eosinophil and neutrophil recruitment into the airways was enhanced in T-bet(-/-) mice but was attenuated in STAT4(-/-) mice and T-bet(-/-)STAT4(-/-) mice. Ag-induced IL-17 production in the airways was also diminished in STAT4(-/-) mice and T-bet(-/-)STAT4(-/-) mice. These results indicate that STAT4 not only plays an indispensable role in T-bet-independent Th1 differentiation but also is involved in the maintenance of Th17 cells and the enhancement of allergic airway inflammation.