From the cradle to the grave: activities of GATA-3 throughout T-cell development and differentiation

Abstract

GATA family transcription factors play multiple vital roles in hematopoiesis in many cell lineages, and in particular, T cells require GATA-3 for execution of several developmental steps. Transcriptional activation of the Gata3 gene is observed throughout T-cell development and differentiation in a stage-specific fashion. GATA-3 has been described as a master regulator of T-helper 2 (Th2) cell differentiation in mature CD4(+) T cells. During T-cell development in the thymus, its roles in the CD4 versus CD8 lineage choice and at the β-selection checkpoint are the best characterized. In contrast, its importance prior to β-selection has been obscured both by the developmental heterogeneity of double negative (DN) 1 thymocytes and the paucity of early T-lineage progenitors (ETPs), a subpopulation of DN1 cells that contains the most immature thymic progenitors that retain potent T-lineage developmental potential. By examining multiple lines of in vivo evidence procured through the analysis of Gata3 mutant mice, we have recently demonstrated that GATA-3 is additionally required at the earliest stage of thymopoiesis for the development of the ETP population. Here, we review the characterized functions of GATA-3 at each stage of T-cell development and discuss hypothetical molecular pathways that mediate these functions.

Fig. 1. A model for T lymphopoiesis

Popular models for lineage specification from HSCs derive from the concept that, as cells mature, they progressively lose differentiation potential. Myeloid, B, and T-lineage potential are shown in orange, blue, and green, respectively. Cells that are committed to the T lineage are shown in dark green. The identity of the thymus homing cells remains controversial. Possible homing cells are shown in dashed lines. GATA-3 is required for the development of ETP, DN4, and CD4 SP T cells in the thymus (magenta arrow). E, erythroid lineage cells; M, myeloid lineage cells; B, B lymphoid lineage cells

Fig. 2. A hypothetical transcriptional hierarchy mediated through and by GATA-3

Factors that regulate Gata3 gene at each stage are shown. Positive regulators are shown in red arrow and negative regulators are shown in blue arrow. Factors that have been shown to directly bind Gata3 gene are shown by a solid line, while other factors are shown with a dashed line. Factors that are regulated by GATA-3 protein positively (red arrow) or negatively (blue arrow) are shown. Genes that have been show to be directly bound by GATA-3 are shown with a solid line, while genes for which evidence for direct regulation is lacking or questionable are shown with dashed lines. Factors shown in gray are suggested from correlative data.