T Helper Cell Differentiation: Regulation by cis Elements and Epigenetics

Abstract

Cytokine loci undergo changes in chromatin structure when naive CD4(+) T cells differentiate into Th1 or Th2 cells and have also been examined for regulatory sequences underlying such changes and their functional correlates. Studies have shown that distal regulatory elements control the Ifng and Th2 cytokine loci and are primary targets for tissue-specific transcription factors, serving as centers for epigenetic changes that mark heritable traits in effector cells. Reports of intra- and, remarkably, interchromosomal interactions between these regulatory elements shed light on the mechanisms by which they regulate gene expression, revealing an extraordinary new picture that conceptually extends our views on how genes are regulated from two to three dimensions. Here, we summarize these recent findings on the role of regulatory elements and their mechanisms of action, which are of broad significance for gene regulation, not only of the immune system but also of many, if not all, coregulated genes.

Histone Acetylation Facilitates Rapid and Robust Memory CD8 T Cell Response through Differential Expression of Effector Molecules (Eomesodermin and Its Targets: Perforin and Granzyme B)

“…Our recent findings demonstrate that the differentially higher expressed genes have high levels of H3K9Ac in their gene loci in memory CD8 T cells and increased H3K9Ac levels after an HDAC inhibitor (Trichostatin A) treatment increases gene expression in naive CD8 T cells (21), providing evidence that histone acetylation may regulate gene expression and function of memory CD8 T cells. In addition, changes in DNA methylation in some of these gene loci have also been reported (20,22,23). There is an inverse correlation between the methylation of the 5ЈUTR and EOMES expression (24) and DNA hypomethylation in the PRF1 promoter increases PRF1 expression (25).…”

How are TH1 and TH2 effector cells made?

“…Interchromosomal interactions opened a completely new avenue in our understanding of gene regulation. This phenomenon now appears to be a general mechanism employed in multiple genetic systems [40].…”

“…Although the Ifnγ and Il4 genes are transcribed in naïve T cells within 3 to 24 hours after initial activation [40], only upon terminal differentiation several days later does strong lineage specific expression occur. This elevated and lineage restricted expression requires increased expression of positively or negatively acting lineage specific transcription factors.…”

Relationship between cytokine expression patterns and clinical outcomes: two population‐based birth cohorts

“…In mouse T cells, remodelling of the chromatin structure within this region occurs when naive T helper cells differentiate into mature Th2 cells, an event not observed during Th1 differentiation 33. It has been proposed that this mechanism is important for the coordinated expression of these two cytokines, also resulting in potentiation of the expression of the two cytokines 34, 35. We speculate that the co‐expressors may have remodelled chromatin structure within this region.…”