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

Naturally arising CD25+CD4+ regulatory T cells (TR 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. TR cells specifically express the transcription factor Foxp3,...

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Bibliographic Details
Published in:Nature 2007-04, Vol.446 (7136), p.685-689
Main Authors: Ono, Masahiro, Ohkura, Naganari, Kitabayashi, Issay, Miyachi, Yoshiki, Nagamura, Yuko, Sakaguchi, Shimon, Yaguchi, Hiroko, Tsukada, Toshihiko, Nomura, Takashi
Format: Article
Language:English
Subjects:
Animals
Binding sites
Biological and medical sciences
Core Binding Factor Alpha 2 Subunit - antagonists & inhibitors
Core Binding Factor Alpha 2 Subunit - genetics
Core Binding Factor Alpha 2 Subunit - metabolism
Cytokines
Forkhead Transcription Factors - genetics
Forkhead Transcription Factors - metabolism
Fundamental and applied biological sciences. Psychology
Fundamental immunology
Gene expression
Gene Expression Regulation
Genetics of the immune response
Humans
Immunobiology
Immunology
Interleukin-2 - genetics
Interleukin-2 - metabolism
Lymphocyte Activation
Mice
Molecular biology
Phenotype
Promoter Regions, Genetic - genetics
Protein Binding
Proteins
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - metabolism
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Summary:Naturally arising CD25+CD4+ regulatory T cells (TR 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. TR cells specifically express the transcription factor Foxp3, a key regulator of TR-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- ), and upregulate TR-cell-associated molecules such as CD25, cytotoxic T-lymphocyte-associated antigen-4, and glucocorticoid-induced TNF-receptor-family-related protein. 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, activates IL-2 and IFN- gene expression in conventional CD4+ T cells through binding to their respective promoters. In natural TR cells, Foxp3 interacts physically with AML1. Several lines of evidence support a model in which the interaction suppresses IL-2 and IFN- production, upregulates TR-cell-associated molecules, and exerts suppressive activity. This transcriptional control of TR-cell function by an interaction between Foxp3 and AML1 can be exploited to control physiological and pathological T-cell-mediated immune responses.
ISSN:0028-0836
1476-4687
1476-4679
DOI:10.1038/nature05673