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J. Biol. Chem., Vol. 283, Issue 1, 128-136, January 4, 2008

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T Helper Cell-specific Regulation of Inducible Costimulator Expression via Distinct Mechanisms Mediated by T-bet and GATA-3^*

From the Singapore Immunology Network Laboratory of Immune Regulation, Agency for Science, Technology and Research, Biopolis 138648, Singapore

Inducible costimulator (ICOS) expression is critical for T cell-mediated immunity. We showed previously that T cell receptor and CD28 coengagement up-regulate ICOS expression in activated T cells via the induction of NFATc2. Here, we examined the regulation of ICOS expression by Th-specific transcription factors T-bet and GATA-3. Overexpression of T-bet or GATA-3 alone could enhance, and NFATc2 could further synergize with either of them to increase, icos transcription. Although T-bet acted on the icos promoter, GATA-3 operated via an icos 3'-un-translated region element. Interestingly, NFATc2 was found to bind promiscuously the icos promoter in developing Th0, Th1, and Th2 cells but became selectively associated with T-bet at the promoter and with GATA-3 at the 3'-untranslated region in fully differentiated Th1 and Th2 cells, respectively. Collectively, our results reveal a temporally evolving circuit in which the non-selectively expressed NFATc2 cooperates with Th-restricted T-bet or GATA-3 to direct transcription of a costimulatory gene via distinct regulatory elements in different Th cells undergoing differentiation.

Received for publication, September 13, 2007 , and in revised form, October 22, 2007.

^* This work was supported by grants from the Biomedical Research Council of the Agency for Science, Technology and Research, Singapore. 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.

¹ To whom correspondence should be addressed: Singapore Immunology Network Laboratory of Immune Regulation, Agency for Science, Technology and Research, Singapore, 8A Biomedical Grove, Immunos Level 3, Biopolis 138648, Singapore. Tel.: 65-6407-0001; Fax: 65-6464-2056; E-mail: lam_kong_peng{at}immunol.a-star.edu.sg.

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