Interleukin (IL)-4-independent Maintenance of Histone Modification of the IL-4 Gene Loci in Memory Th2 Cells

Masakatsu Yamashita,Ryo Shinnakasu,Yukiko Nigo,Motoko Kimura,Akihiro Hasegawa,Masaru Taniguchi,Toshinori Nakayama

doi:10.1074/jbc.m405989200

Abstract

Interleukin (IL)-4-induced STAT6 activation and the subsequent up-regulation of GATA3 are crucial for the induction of chromatin remodeling of the Th2 cytokine gene loci as Th2 cells undergo development. This study probes the role of these molecules in the maintenance of memory Th2 cells. IL-4 was not required to maintain the capability for Th2 cytokine production in in vivo generated antigen-specific memory Th2 cells. Histone H3-K9/14 hyperacetylation and intergenic transcripts associated with the IL-4 gene locus were preserved in the absence of IL-4, but those associated with the IL-13 gene were partially IL-4-dependent. Histone H3-K4 methylation of the IL-13 and IL-4 gene loci was fully preserved in memory Th2 cells and accompanied by memory cell-specific accumulation of Pol II complex to highly restricted sites. Thus, memory Th2 cells maintain a unique Th2-specific remodeled chromatin in the IL-4 and IL-13 gene loci by active molecular events that are IL-4-independent.

Highlights

Interleukin (IL)-4-induced STAT6 activation and the subsequent up-regulation of GATA3 are crucial for the induction of chromatin remodeling of the Th2 cytokine gene loci as Th2 cells undergo development
We compared acetylation status of IFN␥ promoter in effector and memory Th1 cells and found that significant levels of acetylation of the IFN␥ promoter induced in effector Th1 cells were substantially decreased in memory Th1 cells (Supplemental Fig. 2). These results suggest that memory Th1 and Th2 cells possess higher background levels of histone acetylation in all regions tested as compared with naıve T cells, and that Th2 memory cells preserved preferentially increased acetylation of histone H3-K9/14 in the IL-4 and IL-13 gene-related regions
We investigated the molecular basis for the maintenance of Th2 cytokine production in memory Th2 cells using in vivo generated OVA-specific memory Th2 cells

Summary

Introduction

Interleukin (IL)-4-induced STAT6 activation and the subsequent up-regulation of GATA3 are crucial for the induction of chromatin remodeling of the Th2 cytokine gene loci as Th2 cells undergo development. Histone H3-K9/14 associated with the IL-4 and IL-13-related gene loci (CGRE, CNS1, VA enhancer, IL-4p, and IL-13p) were hyperacetylated in both memory Th2 cells and effector Th2 cells compared with freshly isolated naıve DO11.10 TCR Tg CD4 T cells (Fig. 3A).

Results

Conclusion