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International Immunology Advance Access published online on October 11, 2006

International Immunology, doi:10.1093/intimm/dxl102
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© The Japanese Society for Immunology. 2006. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
Received June 22, 2006
Accepted September 13, 2006

Article

Genetic background influences Th cell differentiation by controlling the capacity for IL-2-induced IL-4 production by naive CD4+ T cells

Junji Yagi 1 *, Yutaka Arimura 2, Hiroaki Takatori 3, Hiroshi Nakajima 3, Itsuo Iwamoto 3, and Takehiko Uchiyama 4

1 Department of Microbiology and Immunology, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
2 Department of Microbiology and Immunology, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan; Present address: Inflammatory and Infectious Disease Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
3 Department of Allergy and Clinical Immunology, Chiba University School of Medicine, 1-8-1 Inohara, Chiba City, Chiba 260-8670, Japan
4 Department of Microbiology and Immunology, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan; Institute of Laboratory Animals, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan

* To whom correspondence should be addressed.
Junji Yagi, E-mail: jyagi1{at}research.twmu.ac.jp


   Abstract

Comparative studies using Th2-prone BALB/c and Th1-prone C57BL/6 mice were performed to clarify the influence of genetic background on Th cell differentiation. The results showed IL-4, the production of which is induced by IL-2, to be much more abundantly produced by BALB/c naive CD4+ T cells than by C57BL/6 naive CD4+ T cells, thereby leading to a tendency for differentiation toward Th2 in BALB/c naive CD4+ T cells. This difference in IL-4 production between the two naive CD4+ T cells appeared to be attributable to specific intracellular signaling events. Signal transducer and activator of transcription 5 (STAT5) was preferentially activated by IL-2 in CD4+ T cells developing in BALB/c in contrast to the corresponding cells in C57BL/6. In addition, IL-4 also induced stronger STAT5 activation in CD4+ T cells developing in BALB/c than in those developing in C57BL/6, whereas STAT6 was equally activated in these two cells. Further results supported the involvement of STAT5 in the difference in Th cell differentiation between BALB/c and C57BL/6 naive CD4+ T cells. STAT5A-/- naive CD4+ T cells with the BALB/c genetic background showed markedly less IL-2-induced IL-4 production than BALB/c naive CD4+ T cells. Conversely, forced expression of the constitutively active forms of STAT5A and STAT5B in C57BL/6 naive CD4+ T cells promoted the differentiation of Th2 cells. Thus, our results indicate IL-2-induced IL-4 production by naive CD4+ T cells, in which STAT5 activation is involved and directly controlled by the genetic background, to influence Th cell differentiation in murine strains.

Keywords: BALB/c; C57BL/6; cytokines; STAT5; Th1/Th2 cells.
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