Furuta Shunsuke, Kagami Shin-ichiro, Tamachi Tomohiro, Ikeda Kei, Fujiwara Michio, Suto Akira, Hirose Koichi, Watanabe Norihiko, Saito Yasushi, Iwamoto Itsuo, Nakajima Hiroshi
Department of Allergy and Clinical Immunology, Chiba University Hospital, Chiba, Japan.
J Immunol. 2008 May 15;180(10):6656-62. doi: 10.4049/jimmunol.180.10.6656.
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.
T-bet和STAT4在辅助性T细胞分化中发挥关键作用，尤其是对于Th1细胞。然而，T-bet和STAT4在Th1分化中的相对重要性和冗余性仍不清楚。它们在调节过敏性气道炎症中的独立作用也不清楚。在本研究中，我们通过比较相同遗传背景下的T-bet缺陷（T-bet(-/-)）小鼠、STAT4(-/-)小鼠以及T-bet和STAT4双缺陷（T-bet(-/-)STAT4(-/-)）小鼠来解决这些问题。与野生型小鼠相比，T-bet(-/-)小鼠和STAT4(-/-)小鼠中的Th1分化严重降低，但在T-bet(-/-)小鼠和STAT4(-/-)小鼠中仍可观察到Th1分化。然而，在T-bet(-/-)STAT4(-/-)小鼠中几乎检测不到Th1细胞。相反，T-bet(-/-)小鼠中Th17细胞的维持增强，但在STAT4(-/-)小鼠和T-bet(-/-)STAT4(-/-)小鼠中减少。在体内，抗原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STAT4(-/-)小鼠和T-bet(-/-)STAT4(-/-)小鼠中减弱。抗原诱导的气道中IL-17的产生在STAT4(-/-)小鼠和T-bet(-/-)STAT4(-/-)小鼠中也减少。这些结果表明，STAT4不仅在不依赖T-bet的Th1分化中起不可或缺的作用，而且还参与Th17细胞的维持和过敏性气道炎症的增强。
