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

Andy Hee-Meng Tan,Sharon Yun-Pei Goh,Kong-Peng Lam,Siew-Cheng Wong

doi:10.1074/jbc.m707693200

Abstract

Inducible costimulator (ICOS) expression is critical for T cell-mediated immunity. We showed previously that T cell receptor and CD28 co-engagement 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.

Highlights

IntroductionDespite the extensively characterized role of Inducible costimulator (ICOS) in Thspecific immune responses, it is currently unclear how icos expression is being regulated during Th cell development
Inducible costimulator (ICOS) Is Differentially Expressed in Different Th Cell Subsets—To assess whether ICOS is differentially expressed in various Th cells, we activated primary CD4ϩ T cells with anti-CD3 and anti-CD28 Abs and differentiated them for 8 days under from them
ICOS plays a critical role in the costimulation of T cell responses in mice and humans

Summary

Introduction

Despite the extensively characterized role of ICOS in Thspecific immune responses, it is currently unclear how icos expression is being regulated during Th cell development It is not known whether T-bet and GATA-3 play direct roles in regulating ICOS expression and whether ICOS regulation is subjected to different transcriptional mechanisms in different Th cells. It has been established that upon T cell receptor stimulation, NFAT proteins undergo calcineurin-mediated dephosphorylation and translocate to the nucleus where they cooperate with members of the AP-1 complex to activate target genes such as IL-2. Without their transcriptional partners, the binding of NFAT to gene promoters alone results in T cell anergy [29]. We sought to determine whether the same partnership is invoked to regulate ICOS expression in Th cells

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Conclusion