Common themes emerge in the transcriptional control of T helper and developmental cell fate decisions regulated by the T-box, GATA and ROR families

Abstract

Cellular differentiation requires the precise action of lineage-determining transcription factors. In the immune system, CD4(+) T helper cells differentiate into at least three distinct effector lineages, T helper type 1 (Th1), Th2 and Th17, with the fate of the cell at least in part determined by the transcription factors T-box expressed in T cells (T-bet), GATA-3 and retinoid-related orphan receptor gammat (RORgammat), respectively. Importantly, these transcription factors are members of larger families that are required for numerous developmental transitions from early embryogenesis into adulthood. Mutations in members of these transcription factor families are associated with a number of human genetic diseases due to a failure in completing lineage-specification events when the factor is dysregulated. Mechanistically, there are both common and distinct functional activities that are utilized by T-box, GATA and ROR family members to globally alter the cellular gene expression profiles at specific cell fate decision checkpoints. Therefore, understanding the molecular events that contribute to the ability of T-bet, GATA-3 and RORgammat to define T helper cell lineages can provide valuable information relevant to the establishment of other developmental systems and, conversely, information from diverse developmental systems may provide unexpected insights into the molecular mechanisms utilized in T helper cell differentiation.

Figure 1

T-box, GATA and retinoid-related orphan receptor (ROR) factors play essential roles in the development of (a) T helper cells and (b) other tissues. (a) In this simplified representation, naïve CD4⁺ T cells differentiate into distinct T helper type 1 (Th1), Th2 and Th17 subsets based upon the expression and functional activities of T-bet, GATA-3 and RORγt, respectively. (b) Similarly, during embryogenesis, stem cells require the activities of T-box, GATA and ROR family members to differentiate into distinct lineages such as those that form the heart and pituitary. The asterisk indicates the possible role of RORα in the pituitary. In the development of both effector T helper cells and other tissues, there are many other proteins, including other members of the T-box, GATA and ROR families, that are required. Also, in the case of the heart and pituitary, there are many intermediate steps between the common stem cell and the differentiated tissue. However, it remains striking that members of the same transcription factor families are involved in such disparate developmental decisions as heart, pituitary and T helper cell differentiation.