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

• Published in: The Journal of immunology (1950) 2005-11, Vol.175 (9), p.5981-5985
• Main Authors: Martins, Gislaine A, Hutchins, Anne S, Reiner, Steven L
• Format: Article
• Language: English
• Subjects: Animals; GATA3 Transcription Factor - physiology; Homeodomain Proteins - physiology; Interferon-gamma - biosynthesis; Interferon-gamma - genetics; Interleukin-4 - biosynthesis; Interleukin-4 - genetics; Mice; Mice, Inbred C57BL; Mice, Transgenic; T-Box Domain Proteins; Th1 Cells - physiology; Th2 Cells - physiology; Trans-Activators - physiology; Transcription Factors - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.175.9.5981

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.