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

Summary:  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.