Genetic and epigenetic networks controlling T helper 1 cell differentiation

Abstract

Significant progress has been made during the past years in our understanding of the mechanisms that control the differentiation of naïve CD4(+) T cells into effector T-cell subsets with distinct functional properties. Previous work allowed the identification of key molecules involved in regulating this highly complex process, such as cytokines and their receptors, signal transducers and transcription factors. More recently, the emphasis of research in this field has been to elucidate how the multiplicity of signals is integrated to shape a T helper subset-specific gene-expression program controlling differentiation and effector functions. In this review we will highlight advances that have been made in unravelling the genetic and epigenetic networks controlling differentiation of naïve CD4(+) T cells into interferon-gamma(IFN-gamma)-secreting T helper type 1 (Th1) cells.

Figure 1

Early induction of interleukin-12 receptor β2 (IL12RB2) expression during T helper type 1 (Th1) cell development: a model. The inaccessible chromatin structure at the IL12RB2 locus prevents transcription of this gene in naïve CD4⁺ T cells. T-cell receptor (TCR) signalling is necessary and sufficient to induce the initial opening of the regulatory regions, mediated by the Brahma-related gene (BRG1)/Brahma (BRM)-associated factor (BAF complex) and histone acetylation, resulting in low-level IL12RB2 gene transcription and responsiveness to IL-12. Subsequently, signal transducer and activator of transcription 4 (STAT4) activation is necessary to induce further recruitment of BRG1 and increased histone acetylation that results in high-level IL-12Rβ2 gene transcription and Th1 lineage commitment (from Ref. 16).

Figure 2

The Ifng locus and its epigenetic modifications in naïve CD4, T helper type 1 (Th1) and T helper type 2 (Th2) cells. Composite pattern of conserved non-coding sequences (CNS; grey bar), DNAse I hypersensitivity (downward black arrows), histone H4 acetylation (green circles), histone H3 acetylation (green squares), histone H3 lysine 4 dimethylation (H3K4me2; blue squares), histone H3 lysine 27 dimethylation (H3K27me2; red squares) and cytosine–phosphate–guanosine (CpG) methylation (red stars) at the Ifng locus in naïve CD4, Th1 and Th2 cells. This diagram does not depict quantitative changes of DNAse I hypersensitivity, enrichment for histone modifications and DNA methylation in naive, Th1 and Th2 cells. (Adapted from Ref. compiled with data from Ref. –.) For reasons of clarity, quantitative changes of epigenetic marks have not been depicted.