Regulation of the Ifng locus in the context of T-lineage specification and plasticity

Abstract

Study of the development of distinct CD4(+) T-cell subsets from naive precursors continues to provide excellent opportunities for dissection of mechanisms that control lineage-specific gene expression or repression. Whereas it had been thought that the induction of transcription networks that control T-lineage commitment were highly stable, reinforced by epigenetic processes that confer heritability of functional phenotypes by the progeny of mature T cells, recent findings support a more dynamic view of T-lineage commitment. Here, we highlight advances in the mapping and functional characterization of cis elements in the Ifng locus that have provided new insights into the control of the chromatin structure and transcriptional activity of this signature T-helper 1 cell gene. We also examine epigenetic features of the Ifng locus that have evolved to enable its reprogramming for expression by other T-cell subsets, particularly T-helper 17 cells, and contrast features of the Ifng locus with those of the Il17a-Il17f locus, which appears less promiscuous.

Fig. 1. Developmental pathways of effector CD4⁺ T-cell subsets that can lead to Ifng expression

Following exposure to foreign antigen, naive CD4⁺ T cells are directed towards distinct developmental programs by cytokines that differentially induce lineage-specifying transcription factors (see main text for details). In addition to classical Th1 cells, Th17, iTreg, and Th2 cells can be induced to express IFN-γ under certain conditions. The broken lines associated with the T_fh pathway represent the possibility that these cells branch from developing Th1, Th2, and Th17 precursors rather than directly from naive precursors (123).

Fig. 2. DNase I hypersensitivity profiles of CD4⁺ T cells

At the top of each figure a schematic displays the extended Ifng locus (A) or the Il17a–Il17f locus (B) composed of the gene(s), their associated promoter (P) and numeric descriptions (based on distance from the transcriptional start site) of identified conserved non-coding sequences (CNS). Regions of DNase I hypersensitivity, as determined by DNase-chip, are designated by colored peaks when corresponding to a CNS from resting naive or resting primary Th1, Th2, or Th17 cells. A downward arrow identifies a hypersensitive site that is not within a conserved region. CTCF-binding boundary elements are in red. Transcription factors that are recruited to the indicated conserved elements of each locus are listed. Paler peaks indicate activation-dependent HS sites within CNS elements (e.g. CNS-34 in Naive cells, A) or less intense HS peaks (e.g., +66 site in Naive cells, A)

Fig. 3. DNase I hypersensitivity profiles of IL-12–transitioned Th17 cells

As in Fig. 2, DNase I hypersensitive sites are identified in the Ifng locus (A) and the IL17a–IL17f locus (B) in Th17 cells and in Th17 cells exposed to IL-12 (Th17/IL-12) that exhibit a Th1-like phenotype. Paler peaks indicate activation-dependent HS sites within CNS elements (e.g. CNS-6 in the Th17/IL-12 cells, A).