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

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(1-3). 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(4-7). 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(8-11), activates IL-2 and IFN-gamma 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.