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(American Journal of Pathology. 2003;162:263-271.)
© 2003 American Society for Investigative Pathology

Regular Articles

Development of Colitis in Signal Transducers and Activators of Transcription 6-Deficient T-Cell Receptor -Deficient Mice

A Potential Role of Signal Transducers and Activators of Transcription 6-Independent Interleukin-4 Signaling for the Generation of Th2-Biased Pathological CD4⁺ßßT Cells

Yoshiko Okuda^*, Ichiro Takahashi^*, Jin-Kyung Kim^*, Noriyuki Ohta^*, Kouichi Iwatani^*, Hideki Iijima^*, Yasuyuki Kai^*, Hiroshi Tamagawa^*, Takachika Hiroi^*, Mi-Na Kweon^*, Sunao Kawano, Kiyoshi Takeda^¶, Sizuo Akira^¶, Yutaka Sasaki, Masatsugu Hori and Hiroshi Kiyono^*||

From the Departments of Mucosal Immunology^* and Host Defense,^¶ Research Institute for Microbial Diseases, and the Departments of Internal Medicine and Therapeutics and Clinical Laboratory Science, School of Allied Health Sciences, Faculty of Medicine, Osaka University, Osaka; the Department of Microbiology and Immunology,|| Division of Mucosal Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo; and the Department of Preventive Dentistry and Host Defense, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan

Forbidden CD4⁺ßß T cells, which produce interleukin (IL)-4 predominantly, are a pathological subset in the development of colitis in T-cell receptor chain (TCR)-deficient mice. Stimulation of naive CD4⁺ T cells with IL-4 induces Th2 development via the activation of signal transducers and activators of transcription (STAT) 6. In the present study, we had found that IL-4 enhanced the expression of STAT6 in CD4⁺ßß T cells isolated from TCR^-/- mice with colitis, suggesting that the IL-4 signal in the CD4⁺ßß T cells is mediated by STAT6. To further investigate the role of STAT6 in the development of colitis induced by TCR deficiency, we generated double-deficient mice by crossing TCR^-/- mice and STAT6^-/- mice. Surprisingly, STAT6 deficiency did not result in decreased severity of colitis in TCR^-/- mice. STAT6-deficient CD4⁺ßß T cells produced IL-4 and intraperitoneal injection of anti-IL-4 monoclonal antibody in the nondiseased TCR^-/- and STAT6 double-deficient mice prevented the colitis formation, thus indicating that the cells differentiated into the Th2 phenotype have the ability to mediate the development of the colitis in the absence of STAT6.

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