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Th1 and Type 1 Cytotoxic T Cells Dominate Responses in T-bet Overexpression Transgenic Mice That Develop Contact Dermatitis¹

Kazusa Ishizaki^2,*, Akiko Yamada^2,*, Keigyou Yoh, Takako Nakano^*, Homare Shimohata^*, Atsuko Maeda^*, Yuki Fujioka^*, Naoki Morito^*, Yasuhiro Kawachi, Kazuko Shibuya, Fujio Otsuka, Akira Shibuya and Satoru Takahashi^3,*

^* Department of Anatomy and Embryology, Department of Immunobiology, Biomolecular, and Integrated Medical Sciences, Department of Pathophysiology of Renal Diseases, and Department of Dermatology, Medical Sciences for Control of Pathological Processes, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan

Contact dermatitis in humans and contact hypersensitivity (CHS) in animal models are delayed-type hypersensitivity reactions mediated by hapten-specific T cells. Recently, it has become clear that both CD4⁺ Th1 and CD8⁺ type 1 cytotoxic T (Tc1) cells can act as effectors in CHS reactions. T-bet has been demonstrated to play an important role in Th1 and Tc1 cell differentiation, but little is known about its contribution to CHS. In the present study, we used C57BL/6 mice transgenic (Tg) for T-bet to address this issue. These Tg mice, which overexpressed T-bet in their T lymphocytes, developed dermatitis characterized by swollen, flaky, and scaly skin in regions without body hair. Skin histology showed epidermal hyperkeratosis, neutrophil, and lymphocyte infiltration similar to that seen in contact dermatitis. T-bet overexpression in Tg mice led to elevated Th1 Ig (IgG2a) and decreased Th2 Ig (IgG1) production. Intracellular cytokine analyses demonstrated that IFN- was increased in both Th1 and Tc1 cells. Furthermore, Tg mice had hypersensitive responses to 2,4-dinitrofluorobenzene, which is used for CHS induction. These results suggest that the level of expression of T-bet might play an important role in the development of contact dermatitis and that these Tg mice should be a useful model for contact dermatitis.

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¹ This work was supported by Grants-in-Aid for Young Scientists (B) and Scientific Research (C) from the Ministry of Education, Science, Sports, and Culture and a grant of the Genome Network Project from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

² K.I. and A.Y. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Satoru Takahashi, Department of Anatomy and Embryology, Biomolecular, and Integrated Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan. E-mail address: satoruta{at}md.tsukuba.ac.jp

⁴ Abbreviations used in this paper: Tc, cytotoxic T; CHS, contact hypersensitivity; DNFB, 2,4-dinitrofluorobenzene; LNC, lymph node cell; Tg, transgenic; WT mice, wild-type transgene-negative littermates.