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Overlapping and Distinct Roles of STAT4 and T-bet in the Regulation of T Cell Differentiation and Allergic Airway Inflammation¹

Shunsuke Furuta^2,*,, Shin-ichiro Kagami^2,*,, Tomohiro Tamachi^*, Kei Ikeda^*, Michio Fujiwara^*, Akira Suto^*,, Koichi Hirose^*, Norihiko Watanabe^*, Yasushi Saito, Itsuo Iwamoto and Hiroshi Nakajima^3,*,

^* Department of Allergy and Clinical Immunology, Chiba University Hospital; Department of Clinical Cell Biology and Department of Molecular Genetics, Graduate School of Medicine, Chiba University; and Research Center for Allergy and Clinical Immunology, Asahi General Hospital, Chiba, Japan

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.

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¹ This work was supported in part by grants from Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government.

² S.F. and S.K. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Hiroshi Nakajima, Department of Molecular Genetics, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba 260-8670, Japan. E-mail address: nakajimh{at}faculty.chiba-u.jp

⁴ Abbreviations used in this paper: Th17 cells, IL-17-producing helper T cells; WT, wild type; PAS, periodic acid-Schiff; BALF, bronchoalveolar lavage fluid.