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J. Biol. Chem., Vol. 279, Issue 12, 11408-11416, March 19, 2004

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Akt Is a Neutral Amplifier for Th Cell Differentiation^*

Yutaka Arimura, Fumiko Shiroki¶, Shingo Kuwahara, Hidehito Kato, Umberto Dianzani||, Takehiko Uchiyama, and Junji Yagi

From the Department of Microbiology and Immunology, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan and the ^||Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Medical Sciences, A. Avogadro University of Eastern Piedmont, Novara 28100, Italy

Both CD28 and its relative, inducible costimulator (ICOS), have a binding motif for phosphatidylinositol 3-kinase (PI3K) in their cytoplasmic tail, and the binding of PI3K leads to activation of a serine/threonine kinase, Akt. The role of Akt in cytokine production and helper T (Th) cell differentiation remains obscure. In this study, we found that enforced expression of the constitutively active form (E40K) of Akt rendered CD4⁺ T cells activated. Wild-type of Akt and E40K promoted Th1 cell differentiation in C57BL/6-derived and Th1-polarized BALB/c-derived CD4⁺ T cells, while both promoted Th2 cell differentiation in BALB/c-derived and Th2-polarized C57BL/6 CD4⁺ T cells. E40K also facilitated Th1 differentiation in CD4⁺ T cells from IL-4-deficient mice with the BALB/c background. E40K up-regulated expression of NF-AT and c-Myb, which may be related to the augmentation of cytokine production by E40K. These findings indicate that the mechanism by which Akt augments cytokine production via CD28 and ICOS is Th cell type-specific and reflects the intracellular status affected by the cytokine milieu. We conclude that Akt is a neutral amplifier of T cell activation and Th differentiation.

Received for publication, August 15, 2003 , and in revised form, December 4, 2003.

^* This work was supported in part by grants from the Ministry of Education, Science, Sports and Culture of Japan; the Ministry of Public Welfare of Japan; the research fund of professor emeritus Dr. Kiyoko Kurokawa; and the Associazione Italiana Ricerca sul Cancro (AIRC, Milan, Italy). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Present address: Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan.

To whom correspondence and reprint requests should be addressed: Dept. of Microbiology and Immunology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. Tel: 81-3-3353-8111; Fax: 81-3-5269-7411; E-mail: arimura{at}research.twmu.ac.jp.

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