Helper T-cell identity and evolution of differential transcriptomes and epigenomes

Abstract

CD4(+) T cells are critical for the elimination of an immense array of microbial pathogens. Among the ways they accomplish this task is to generate progeny with specialized, characteristic patterns of gene expression. From this perspective, helper cells can be viewed as pluripotent precursors that adopt distinct cell fates. Although there are aspects of helper cell differentiation that can be modeled as a classic cell fate commitment, CD4(+) T cells also maintain considerable flexibility in their transcriptional program. This makes sense in terms of host defense, but raises the question of how these remarkable cells balance both these requirements, a high degree of specific gene expression and the capacity for plasticity. In this review, we discuss recent advances in our understanding of CD4(+) T-cell specification, focusing on how genomic perspectives have influenced our views of these processes. The relative contributions of sensors of the cytokine milieu, especially the signal transducer and activator of transcription family transcription factors, 'master regulators', and other transcription factors are considered as they relate to the helper cell transcriptome and epigenome.

Fig. 1. ‘Classical’ model of the role of master regulators for CD4⁺ T-cell differentiation

From the classical monolithic perspective, each helper cell subset expresses a lineage-defining ‘master regulator’ transcription factor, which is necessary and sufficient to induce each subsets specific gene-expression.

Fig. 2. Models for co-expression of master regulators

Recent advances have argued for a more nuanced view of master regulators. Abundant data indicate that helper cells often express more than one master regulator. In this regard, one can view expression of master regulators in three ways. (A) “Subspecialization” model. Co-expression of two master regulators is functionally important for Foxp3⁺ Treg cells. The functional responses of Treg cells can be specialized or targeted based on the expression of a master regulator co-expressed with Foxp3⁺. Each sub-population shows the specific repressive activity for each helper T-cell subset. (B) ‘Flexibility’ model. Recent studies have also revealed greater flexible behavior of helper T-cell subsets. Epigenetic modifications facilitate flexible co-expression of transcription factors, and consequently the co-expression of non-canonical cytokines. In principle, such a scenario permits flexible responses to offending pathogens, in this way host defense may be maximized. (C) ‘Balanced (Competition)’ model. In the case of T-bet and Bcl6, these factors are co-expressed, but are functionally antagonistic. From this perspective, responses are constrained or tuned in response to exogenous factors. In reality, it is not just two factors that are regulated but probably dozens. To truly understand the complexity of helper T-cell specification, it is more appropriate to think about highly regulated expression of networks of transcription factors responding to exogenous and endogenous signals.

Fig. 3. Model for the role of pioneering factors and master regulators during CD4⁺ T-cell differentiation

Various perturbations like TCR occupancy or the cytokine milieu can induce ‘pioneering factors’ and activate different STATs, which are indispensable for establishing the genomic epigenetic landscapes of developing helper T cells and dictating the accessibility of key target genes. New data argue that helper T-cell master regulators do not have major effects on the chromatin organization of helper T cells. On the contrary, they have focused actions on key genes which are crucial for lineage specificity or limit alternative fates. Helper T-cell master regulators may be better viewed as critical modulators but not drivers of the chromatin architecture underlying helper cell identity.