Genome-Wide Gene Expression Profiling Revealed a Critical Role for GATA3 in the Maintenance of the Th2 Cell Identity

Tetsuya Sasaki,Yutaka Suzuki,Yukiko Watanabe,Toshinori Nakayama,Hiroyuki Hosokawa,Yasumasa Ogawa,Atsushi Onodera,Shu Horiuchi,Hitoshi Tanaka,Junji Yamashita

doi:10.1371/journal.pone.0066468

Tetsuya Sasaki, Yutaka Suzuki + Show 8 more

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https://doi.org/10.1371/journal.pone.0066468

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Abstract

Functionally polarized CD4+ T helper (Th) cells such as Th1, Th2 and Th17 cells are central to the regulation of acquired immunity. However, the molecular mechanisms governing the maintenance of the polarized functions of Th cells remain unclear. GATA3, a master regulator of Th2 cell differentiation, initiates the expressions of Th2 cytokine genes and other Th2-specific genes. GATA3 also plays important roles in maintaining Th2 cell function and in continuous chromatin remodeling of Th2 cytokine gene loci. However, it is unclear whether continuous expression of GATA3 is required to maintain the expression of various other Th2-specific genes. In this report, genome-wide DNA gene expression profiling revealed that GATA3 expression is critical for the expression of a certain set of Th2-specific genes. We demonstrated that GATA3 dependency is reduced for some Th2-specific genes in fully developed Th2 cells compared to that observed in effector Th2 cells, whereas it is unchanged for other genes. Moreover, effects of a loss of GATA3 expression in Th2 cells on the expression of cytokine and cytokine receptor genes were examined in detail. A critical role of GATA3 in the regulation of Th2-specific gene expression is confirmed in in vivo generated antigen-specific memory Th2 cells. Therefore, GATA3 is required for the continuous expression of the majority of Th2-specific genes involved in maintaining the Th2 cell identity.

Highlights

Naıve CD4 T cells have the capacity to differentiate into several alternative cell types, the best characterized of which are Th1, Th2 and Th17 cells [1]
Selection of Th2-specific Inducible Genes To investigate the role of GATA3 in the induction and maintenance of Th2 cell identity, we used effector Th2 cells and fully developed Th2 cells, respectively
We performed a microarray analysis in effector Th2 and fully developed Th2 cells with GATA3 knockdown in order to understand the role of GATA3 in the maintenance of the Th2 cell phenotype

Summary

Introduction

Naıve CD4 T cells have the capacity to differentiate into several alternative cell types, the best characterized of which are Th1, Th2 and Th17 cells [1]. Th1 cells are crucial for obtaining protection against viruses and intracellular pathogens and Th2 cells are required for the removal of extracellular parasites. Th1 cells are involved in the pathogenesis of tissue-specific autoimmune diseases, while Th2 cells are responsible for allergic diseases such as asthma. Th17 cells function in the immune response to extracellular bacteria and participate in the development of inflammatory bowel diseases. Several master transcription factors that regulate Th1/Th2/Th17 cell differentiation have been identified. The generation of Th2 cells requires IL-4, which leads to STAT6 phosphorylation [3] and the upregulation of GATA3, the key regulator of Th2 development [4,5]. Th17 development is thought to be dependent on the lineage-specific transcription factor retinoic acid-related orphan receptor (ROR) ct [6,7]

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