Foxo: in command of T lymphocyte homeostasis tolerance

Immunology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Trends in Immunology (Impact Factor: 12.03). 01/2011; 32(1):26-33. DOI: 10.1016/
Source: PubMed

ABSTRACT The forkhead box O (Foxo) family of transcription factors consists of the mammalian orthologs of the Caenorhabditis elegans longevity protein Daf-16, and has an evolutionarily conserved function in the regulation of nutrient sensing and stress responses. Recent studies have shown that Foxo proteins control expression of immune system-specific genes such as Il7ra in naïve T cells and Foxp3 in regulatory T cells, which are crucial regulators of T cell homeostasis and tolerance. These findings reveal that the ancient Foxo pathway has been co-opted to regulate highly specialized T cell activities. The Foxo pathway probably enables a diverse and self-tolerant population of T cells in the steady state, which is an important prerequisite for the establishment of a functional adaptive immune system.

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    • "A number of other sequence-specific transcription factors have also been implicated in Treg development and function. These include the factors that promote FoxP3 expression during development or homoeostasis (such as FOXO, NF-kb, GATA3 and FOXP3 itself) and those that direct Treg functional specialization in response to inflammatory cues (such as T-BET, IRF4 and STAT3 selectively required for Tregs to suppress Th1-, Th2-and Th17-type inflammation, respectively) (Chaudhry et al, 2009; Koch et al, 2009; Long et al, 2009; Zheng et al, 2009; Kerdiles et al, 2010; Ouyang et al, 2010; Zheng et al, 2010; Ouyang and Li, 2011; Wang et al, 2011). Much less is known regarding the transcription programme that controls Treg activation, even though Treg activation is essential for Treg function. "
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    ABSTRACT: Treg activation in response to environmental cues is necessary for regulatory T cells (Tregs) to suppress inflammation, but little is known about the transcription mechanisms controlling Treg activation. We report that despite the known proinflammatory role of the chromatin-remodelling factor BRG1 in CD4 cells, deleting Brg1 in all αβ T cell lineages led to fatal inflammation, which reflected essential roles of BRG1 in Tregs. Brg1 deletion impaired Treg activation, concomitant with the onset of the inflammation. Remarkably, as the inflammation progressed, Tregs became increasingly activated, but the activation levels could not catch up with the severity of inflammation. In vitro assays indicate that BRG1 regulates a subset of TCR target genes including multiple chemokine receptor genes. Finally, using a method that can create littermates bearing either a tissue-specific point mutation or deletion, we found the BRG1 ATPase activity partially dispensable for BRG1 function. Collectively, these data suggest that BRG1 acts in part via remodelling-independent functions to sensitize Tregs to inflammatory cues, thus allowing Tregs to promptly and effectively suppress autoimmunity.
    The EMBO Journal 01/2013; 32(3). DOI:10.1038/emboj.2012.350 · 10.75 Impact Factor
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    • "During the review of this manuscript, and consistent with this contention, two reports appeared showing that Foxo1 plays a role in the direct transcriptional control of Foxp3 (Ouyang et al., 2010; Harada et al., 2010). We note however, that within the population of Foxp3 + Foxo1 deficient T cells, the amount of Foxp3 per cell was only marginally decreased. "
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