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* Cell Biology Institute, Research Center, Hayashibara Biochemical Laboratories, Fujisaki, Okayama, Japan; and
Kurashiki Medical Center, Bakuro-cho, Kurashiki, Japan
STAT5 molecules are key components of the IL-2 signaling pathway, the deficiency of which often results in autoimmune pathology due to a reduced number of CD4+CD25+ naturally occurring regulatory T (Treg) cells. One of the consequences of the IL-2-STAT5 signaling axis is up-regulation of FOXP3, a master control gene for naturally occurring Treg cells. However, the roles of STAT5 in other Treg subsets have not yet been elucidated. We recently demonstrated that IL-2 enhanced IL-10 production through STAT5 activation. This occurred in two types of human Treg cells: a novel type of umbilical cord blood-derived Treg cell, termed HOZOT, and Tr1-like Treg cells, IL-10-Treg. In this study, we examined the regulatory mechanisms of IL-10 production in these Treg cells, focusing specifically on the roles of STAT5. By performing bioinformatic analysis on the IL-10 locus, we identified one STAT-responsive element within intron 4, designated I-SRE-4, as an interspecies-conserved sequence. We found that I-SRE-4 acted as an enhancer element, and clustered CpGs around the I-SRE-4 were hypomethylated in IL-10-producing Treg cells, but not in other T cells. A gel-shift analysis using a nuclear extract from IL-2-stimulated HOZOT confirmed that CpG DNA methylation around I-SRE-4 reduced STAT5 binding to the element. Chromatin immunoprecipitation analysis revealed the in situ binding of IL-2-activated STAT5 to I-SRE-4. Thus, we provide molecular evidence for the involvement of an IL-2-STAT5 signaling axis in the expression of IL-10 by human Treg cells, an axis that is regulated by the intronic enhancer, I-SRE-4, and epigenetic modification of this element.
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 Address correspondence and reprint requests to Dr. Shuji Nakamura, Cell Biology Institute, Research Center, Hayashibara Biochemical Laboratories, 675-1 Fujisaki, Okayama 702-8006, Japan. E-mail address: shnakamu{at}hayashibara.co.jp
2 Abbreviations used in this paper: Treg, regulatory T; ARRE, Ag receptor-responsive elements; ChIP, chromatin immunoprecipitation; CNS, conserved noncoding sequences; conT, conventional T; DC, dendritic cell; HS, hypersensitivity; I-SRE-4, STAT-responsive element within intron 4; nTreg, naturally occurring regulatory T; P-SRE, STAT-responsive element within proximal region; pAb, polyclonal Ab; rVISTA, Regulatory Visualization Tools for Alignment; SRE, STAT-responsive element; TSS, transcription start site; UCB, umbilical cord blood.
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