We are at a very special time, and probably turning point, in our understanding of the sequences of events that govern the differentiation of naïve CD4 T cells into T helper functional subsets.
There have been three major papers published this year in Cell and that will change our view on the role and function of the so-called “master transcription factors”. These include for example, Foxp3 (regulatory T cells), T-bet (Th1 cells), GATA-3 (Th2 cells) and RORgamma t (Th17 cells). Since the discovery of these specific transcription factors, there is still a large incertitude about how they work, individually or in combination, in the global transcriptional program that control T helper specification and function.
Transcription initiation at strategic sites requires mechanisms for making specific genic regions accessible to appropriate regulators. In the development of specific program of differentiation and acquisition of selective effector functions, there is integration, cooperation and retro-control between expression of transcription factors and the chromatin status (called epigenetic) that give access of these same transcription factors to certain strategic loci. But, which events come first and how is this loop regulated is still very much unclear.
For instance do these master transcription factors control epigenetic landscape on critical loci, such as cytokines and other transcription regulators that are specific to each T helper population? Or is there upstream events that modify the chromatin status to allow these master transcription factors to bind and induce transcription on specific loci?
The three following papers shed new light on these mechanisms. They show that the so called “master” transcription factors in fact act rather late during the differentiation program and surprisingly after the chromatin has been already remodeled by other “pioneer” regulators.
Robert Samstein in Rudensky’s lab shows that Foxp3 – the indispensable transcription factor that specifies identity and function of regulatory T cells – controls transcription NOT through modification of the chromatin landscape BUT by exploiting existing enhancers and promoters newly established by “pioneer” cofactors (including NFAT/AP1 or FOXO1) in precursor cells.
Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification.
Maria Ciofani from Littman’s lab demonstrated that RORgamma t, only plays a deterministic role at key loci after the pioneer cofactors BATF and IRF4 cooperatively initiated changes in chromatin accessibility.
A validated regulatory network for Th17 cell specification.
Golnaz Vahedi from O’Shea’s lab provides evidence for STATs as critical chromatin modifiers that act prior to T-bet or GATA-3 during Th1 or Th2 polarisation respectively. Since STAT are directly linked to signaling through cytokine receptor the STAT can be viewed as key environmental sensors in dynamically molding the specialized enhancer architecture of differentiating cells.
STATs Shape the Active Enhancer Landscape of T Cell Populations.
In conclusion, I can only strongly advice anyone interested in T cell differentiation to read these seminal papers. However, we have to tune down our excitement. Although these papers drastically changed our understanding of the mechanism of action of master regulators, there is still a long way to go determine the first events that control chromatin remodeling and the consequent positioning of these of master regulators on strategic loci, and especially during in vivo T cell responses.