Novel Foxo1-dependent transcriptional programs control T reg cell function

Ouyang, W., Liao, W., Luo, C. T., Yin, N., Huse, M., Kim, M. V., Peng, M., Chan, P., Ma, Q., Mo, Y., Meijer, D., Zhao, K., Rudensky, A. Y., Atwal, G., Zhang, M. Q., Li, M. O. (November 2012) Novel Foxo1-dependent transcriptional programs control T reg cell function. Nature, 491 (7425). pp. 554-559.

Abstract

Regulatory T (T(reg)) cells, characterized by expression of the transcription factor forkhead box P3 (Foxp3), maintain immune homeostasis by suppressing self-destructive immune responses. Foxp3 operates as a late-acting differentiation factor controlling T(reg) cell homeostasis and function, whereas the early T(reg)-cell-lineage commitment is regulated by the Akt kinase and the forkhead box O (Foxo) family of transcription factors. However, whether Foxo proteins act beyond the T(reg)-cell-commitment stage to control T(reg) cell homeostasis and function remains largely unexplored. Here we show that Foxo1 is a pivotal regulator of T(reg )cell function. T(reg) cells express high amounts of Foxo1 and display reduced T-cell-receptor-induced Akt activation, Foxo1 phosphorylation and Foxo1 nuclear exclusion. Mice with T(reg)-cell-specific deletion of Foxo1 develop a fatal inflammatory disorder similar in severity to that seen in Foxp3-deficient mice, but without the loss of T(reg) cells. Genome-wide analysis of Foxo1 binding sites reveals ~300 Foxo1-bound target genes, including the pro-inflammatory cytokine Ifng, that do not seem to be directly regulated by Foxp3. These findings show that the evolutionarily ancient Akt-Foxo1 signalling module controls a novel genetic program indispensable for T(reg) cell function.

Item Type:	Paper
Subjects:	bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
CSHL Authors:	Atwal, Gurinder Singh
Communities:	CSHL labs > Atwal lab CSHL Cancer Center Program > Cancer Genetics
Depositing User:	Matt Covey
Date:	22 November 2012
Date Deposited:	29 Jan 2013 15:15
Last Modified:	14 Oct 2015 19:45
PMCID:	PMC3771531
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/27016

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