Figure 1.

Current schedule of T-helper-cell differentiation. When naïve CD4⁺TCRαβ ⁺ T lymphocytes, classified by their low expression of CD44, absence of CD25, and high levels of CD62L, encounter their cognate antigens, they can differentiate into several previously identified effector subsets. It is likely that several “master” transcription factors, individually required for T-cell differentiation towards one of the end effector stages, are initially expressed upon engagement of the TCR with costimulatory receptors. Each transcription factor drives a specific set of genes required for lineage commitment and the expression of signature cytokines and negatively affects alternative pathways. However, the local microenvironment is the driving force that determines the outcome of the differentiation course. Th1 cells are established in the presence of IFNγ and IL12 and signaling via STAT1 and STAT4, resulting in the expression of the master transcription factor T bet. Th2 cells depend on IL4 and STAT6 for the increased expression of GATA3, whereas the simultaneous presence of TGFβ results in the development of Th9 cells, utilizing an undefined master transcription factor. The presence of TGFβ, with IL2 signaling via STAT5, is known to generate, at least in vitro, inducible Treg, which utilize FOXP3 like those Treg generated in the thymus. Again, it is TGFβ in combination with IL6 signaling via STAT3 that drives the expression of RORγt, resulting in the differentiation of Th17 cells. However, the initiation of the developmental program of these T helper subsets may not be completed in the presence of only these driving cytokines. Several additional factors may be required for their subsequent functional maturation or may be responsible for the fine tuning of their effector phases. Several of these factors are indicated, together with the characteristic cytokine profiles of each subset (adapted from [54]).