1. Howard Hughes Medical Institute,
2. Department of Immunology, University of Washington, Seattle, Washington 98195, USA
3. Present address: Amgen Corporation, Seattle, Washington 98101, USA.

Correspondence to: Alexander Y. Rudensky^1,2 Correspondence and requests for materials should be addressed to A.Y.R. (Email: aruden@u.washington.edu).

Abstract

Transcription factor Foxp3 (forkhead box P3), restricted in its expression to a specialized regulatory CD4⁺ T-cell subset (T_R) with a dedicated suppressor function, controls T_R lineage development. In humans and mice, Foxp3 deficiency results in a paucity of T_R cells and a fatal breach in immunological tolerance, causing highly aggressive multi-organ autoimmune pathology^{1, 2, 3}. Here, through genome-wide analysis combining chromatin immunoprecipitation with mouse genome tiling array profiling, we identify Foxp3 binding regions for 700 genes and for an intergenically encoded microRNA. We find that a large number of Foxp3-bound genes are up- or downregulated in Foxp3⁺ T cells, suggesting that Foxp3 acts as both a transcriptional activator and repressor. Foxp3-mediated regulation unique to the thymus affects, among others, genes encoding nuclear factors that control gene expression and chromatin remodelling. In contrast, Foxp3 target genes shared by the thymic and peripheral T_R cells encode primarily plasma membrane proteins, as well as cell signalling proteins. Together, our studies suggest that distinct transcriptional sub-programmes implemented by Foxp3 establish T_R lineage during differentiation and its proliferative and functional competence in the periphery.

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