Transcriptional Activators of Helper T Cell Fate Are Required for Establishment but Not Maintenance of Signature Cytokine Expression

Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
The Journal of Immunology (Impact Factor: 4.92). 12/2005; 175(9):5981-5. DOI: 10.4049/jimmunol.175.9.5981
Source: PubMed


The stability of helper T cell fates is not well understood. Using conditional introduction of dominant-negative factors, we now show that T-bet and GATA-3 are far more critical in establishment than maintenance of IFN-gamma and IL-4 activity during Th1 and Th2 maturation, respectively. We also show that a genetic interaction between T-bet and its target Hlx seems to be required for Th1 maturation, but that Hlx may also be dispensable for maintenance of a transcriptionally permissive ifng gene. In parallel to progressive activator independence in the permissive lineage, the ifng gene becomes more recalcitrant to switching as the forbidden lineage matures. T-bet plus Hlx can disrupt ifng silencing when introduced into developing Th2 cells, but they fail to perturb ifng silencing in mature Th2 cells. In contrast, a hypermorphic allele of T-bet can reverse silencing of the ifng gene in mature Th2 cells. These results suggest that signature gene activity of helper T cells is initially plastic but later becomes epigenetically fixed and offer an initial strategy for inducing mature cells to switch their fate.