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Martins, G.A., Hutchins, A.S. & Reiner, S.L. Transcriptional activators of helper T cell fate are required for establishment but not maintenance of signature cytokine expression. J. Immunol. 175, 5981-5985

Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
The Journal of Immunology (Impact Factor: 5.36). 12/2005; 175(9):5981-5. DOI: 10.4049/jimmunol.175.9.5981
Source: PubMed

ABSTRACT 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.

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    • "Thus, T cells that can remain quiescent in the peripheral blood for months or years may maintain the epigenetic state of sets of genes that were previously induced. Additionally, genes involved in both Th 1 and Th 2 responses are thought to be available for induction and only become epigenetically fixed once Th 1 /Th 2 switching has occurred (Martins et al. 2005). For the subset of genes in T cells that are induced at the level of transcription and epigenetic modification, such as CDC20 and IRF4, we observed an increase in the levels of active histone marks at the TSS and sometimes throughout the body of the gene. "
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    • "All other transductions were carried out in cells from wild-type Balb/C mice. Cell culture and transductions were carried out as described (Martins et al., 2005). "
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    • "The binding of T-bet alone is sufficient for IFN-γ expression, although the effect can be enhanced by interactions with other transcription factors. T-bet induces expression of the transcription factor H2.0-like homeobox (Hlx), and thereafter interacts with Hlx to induce higher levels of IFN-γ (Martins et al., 2005; Mullen et al., 2002). To enhance further IFN-γ production, T-bet interacts with the transcription factor E26 transformation-specific (Ets)-1 in fully differentiated Th1 cells, and this interaction further stabilizes the Th1 phenotype. "
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