Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1 : Abstract : Nature

Nature 446, 685-689 (5 April 2007) | doi:10.1038/nature05673; Received 12 December 2006; Accepted 9 February 2007; Published online 21 March 2007

Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1

Masahiro Ono^1,^2,⁶, Hiroko Yaguchi^3,⁶, Naganari Ohkura^3,⁶, Issay Kitabayashi⁴, Yuko Nagamura³, Takashi Nomura¹, Yoshiki Miyachi², Toshihiko Tsukada³ & Shimon Sakaguchi^1,⁵

Department of Experimental Pathology, Institute for Frontier Medical Sciences, and
Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
Tumor Endocrinology Project, and,
Molecular Oncology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan
Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Kawaguchi 332-0012, Japan
These authors contributed equally to this work.

Correspondence to: Shimon Sakaguchi^1,⁵ Correspondence and requests for materials should be addressed to S.S. (Email: shimon@frontier.kyoto-u.ac.jp).

Naturally arising CD25⁺CD4⁺ regulatory T cells (T_R cells) are engaged in the maintenance of immunological self-tolerance and immune homeostasis by suppressing aberrant or excessive immune responses, such as autoimmune disease and allergy^1,^2,³. T_R cells specifically express the transcription factor Foxp3, a key regulator of T_R-cell development and function. Ectopic expression of Foxp3 in conventional T cells is indeed sufficient to confer suppressive activity, repress the production of cytokines such as interleukin-2 (IL-2) and interferon-gamma (IFN- gamma ), and upregulate T_R-cell-associated molecules such as CD25, cytotoxic T-lymphocyte-associated antigen-4, and glucocorticoid-induced TNF-receptor-family-related protein^4,^5,^6,⁷. However, the method by which Foxp3 controls these molecular events has yet to be explained. Here we show that the transcription factor AML1 (acute myeloid leukaemia 1)/Runx1 (Runt-related transcription factor 1), which is crucially required for normal haematopoiesis including thymic T-cell development^8,^9,^10,¹¹, activates IL-2 and IFN- gene expression in conventional CD4⁺ T cells through binding to their respective promoters. In natural T_R cells, Foxp3 interacts physically with AML1. Several lines of evidence support a model in which the interaction suppresses IL-2 and IFN- gamma production, upregulates T_R-cell-associated molecules, and exerts suppressive activity. This transcriptional control of T_R-cell function by an interaction between Foxp3 and AML1 can be exploited to control physiological and pathological T-cell-mediated immune responses.

Letter