Molecular mechanisms by which T-bet regulates T-helper cell commitment

Abstract

Current research suggests that a number of newly identified T-helper cell subsets retain a degree of context-dependent plasticity in their signature cytokine expression patterns. To understand this process, a major challenge is to determine the molecular mechanisms by which lineage-defining transcription factors regulate gene expression profiles in T-helper cells. This mechanistic information will aid in our interpretation of whether a T-helper cell state that expresses or retains the capacity to re-express a combination of lineage-defining transcription factors will have a stable or more flexible gene expression profile. Studies examining the developmental T-box transcription factor T-bet demonstrate the powerful information that is gained from combining in vivo analysis with basic biochemical and molecular mechanism approaches. Significantly, T-bet's ability to physically recruit epigenetic modifying complexes, in particular a Jmjd3 H3K27-demethylase and a Set7/9 H3K4-methyltransferase complex, to its target genes allows T-bet to effectively reverse and establish new epigenetic states. This observation suggests that until T-bet is permanently extinguished, T-helper cells will retain some plasticity toward a T-helper 1-like program. Therefore, insight into the complexity of T-helper cell commitment decisions will be aided by determining the molecular mechanisms for lineage-defining transcription factors.

Fig. 1. T-bet interacts with H3K27-demethylase and H3K4-methyltransferase complexes in helper T-cell differentiation

In naive helper T cells (green), loci that are expressed upon differentiation are kept in a repressed epigenetic state (i.e. H3K27me3). T-bet is able to physically recruit an H3K27-demethylase complex (such as Jmjd3) to its target loci during T-helper cell differentiation to effectively reverse the repressive epigenetic state. Subsequently or alternatively in a simultaneous manner, T-bet has the ability to physically interact with and recruit a permissive H3K4-methyltransferase complex (such as Set7/9) to target genes to establish a permissive epigenetic environment (i.e. H3K4me2) compatible with transcription. T-bet's ability to influence the epigenetic environment of the cell gives it the potential to alter the expression of its target genes in any of the T-helper cells in which it is expressed (see Fig. 2).

Fig. 2. Model for how T-bet expression patterns regulate T-helper cell commitment

T-bet has the ability to recruit H3K27-demethylase and H3K4-methyltransferase complexes to its target genes to establish their epigenetic profile. Therefore, if T-bet is expressed, or re-expressed in response to an environmental stimuli, a Th1-like epigenetic signature will be established in the cell. Illustrated here is a gradient model for helper T cell commitment based upon the levels of T-bet (shaded red box). The epigenetic modification at the Tbx21 locus (the gene that encodes T-bet) can be contained within either a permissive (green), repressive (red), or a poised, bivalent (red and green) state in various helper T-cell populations. Importantly, until the Tbx21 locus is permanently extinguished in repressive chromatin, T-bet has the potential to be re-expressed and alter the epigenetic profile of the cell to contain a Th1-like signature. This model is focused on T-bet, but as more studies assess the functional capabilities of the other important transcription factors in T-helper cells, similar and overlapping gradients may exist for their mechanistic role in commitment decisions as well.