A multiply redundant genetic switch 'locks in' the transcriptional signature of regulatory T cells

Abstract

The transcription factor Foxp3 participates dominantly in the specification and function of Foxp3(+)CD4(+) regulatory T cells (T(reg) cells) but is neither strictly necessary nor sufficient to determine the characteristic T(reg) cell signature. Here we used computational network inference and experimental testing to assess the contribution of other transcription factors to this. Enforced expression of Helios or Xbp1 elicited distinct signatures, but Eos, IRF4, Satb1, Lef1 and GATA-1 elicited exactly the same outcome, acting in synergy with Foxp3 to activate expression of most of the T(reg) cell signature, including key transcription factors, and enhancing occupancy by Foxp3 at its genomic targets. Conversely, the T(reg) cell signature was robust after inactivation of any single cofactor. A redundant genetic switch thus 'locked in' the T(reg) cell phenotype, a model that would account for several aspects of T(reg) cell physiology, differentiation and stability. PMID: 22961053 Funding information This work was supported by: NIAID NIH HHS, United States Grant ID: R24 AI072073 NIAID NIH HHS, United States Grant ID: R01 AI051530 NIDDK NIH HHS, United States Grant ID: T32 DK7260 Canadian Institutes of Health Research, Canada NIAID NIH HHS, United States Grant ID: 3R24AI072073-03S1 NIGMS NIH HHS, United States Grant ID: T32 GM007753 NIAID NIH HHS, United States Grant ID: R37 AI051530 NIAID NIH HHS, United States Grant ID: AI072073 NIAID NIH HHS, United States Grant ID: AI051530 More Less keyboard_arrow_down

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