1. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA
2. Department of Biology,
3. Department of Electrical Engineering and Computer Science,
4. Biological Engineering Division,
5. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA
6. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
7. Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
8. These authors contributed equally to this work

Correspondence to: Harald von Boehmer^6,7Richard A. Young^1,2 Correspondence and requests for materials should be addressed to R.A.Y. (Email: young@wi.mit.edu) or H.v.B. (Email: Harald_von_Boehmer@dfci.harvard.edu).

Abstract

Foxp3⁺CD4⁺CD25⁺ regulatory T (T_reg) cells are essential for the prevention of autoimmunity^{1, 2}. T_reg cells have an attenuated cytokine response to T-cell receptor stimulation, and can suppress the proliferation and effector function of neighbouring T cells^{3, 4}. The forkhead transcription factor Foxp3 (forkhead box P3) is selectively expressed in T_reg cells, is required for T_reg development and function, and is sufficient to induce a T_reg phenotype in conventional CD4⁺CD25^- T cells^{5, 6, 7, 8}. Mutations in Foxp3 cause severe, multi-organ autoimmunity in both human and mouse^{9, 10, 11}. FOXP3 can cooperate in a DNA-binding complex with NFAT (nuclear factor of activated T cells) to regulate the transcription of several known target genes¹². However, the global set of genes regulated directly by Foxp3 is not known and consequently, how this transcription factor controls the gene expression programme for T_reg function is not understood. Here we identify Foxp3 target genes and report that many of these are key modulators of T-cell activation and function. Remarkably, the predominant, although not exclusive, effect of Foxp3 occupancy is to suppress the activation of target genes on T-cell stimulation. Foxp3 suppression of its targets appears to be crucial for the normal function of T_reg cells, because overactive variants of some target genes are known to be associated with autoimmune disease.

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