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

Abstract

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. 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. 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-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.

Differential effects of inhibition of bone morphogenic protein (BMP) signalling on T‐cell activation and differentiation

“…First, DM inhibited known targets of BMP signalling including SMAD1/5/ 8. Second, DM suppressed the transcription of IL2, a RUNX1-target gene [15]. Consistently, we have found that BMP signalling increased the level of phorsphorylation of RUNX1 protein, while DM decreased it.…”

“…6). We previously reported that RUNX1 was involved in IL-2 transcription, and that knockdown of RUNX1 completely suppressed IL-2 production in Jurkat cells [15]. Thus, it is interesting that the suppression of IL-2 by DM is coupled with the decrease of the phosphorylated form of RUNX1.…”

“…CD4 1 T cells were isolated and cultured as previously described [15]. For CFSE dilution assay, magnetically sorted mouse CD25 À CD4 1 T cells were labeled with 3 mM CFSE (Dojindo and Invitrogen).…”

“…First, IL-2 production is the crucial mechanism of T-cell activation. Second, IL2 transcription is known to be regulated by several key transcription factors, one of which is AML1/ RUNX1, a well-established downstream target of BMP signalling in hematopoietic lineage cells [8,14,15].…”

“…As AML/RUNX proteins are reported to be involved in BMP signalling in other tissues such as hematopoitic stem cells [8] and RUNX1 is reported as an important transcription factor for T-cell function including IL-2 production [15], we investigated the molecular mechanism of BMP signalling by analysing RUNX1. The phosphorylated form of RUNX1 with phosphorylation sites including Ser249 is believed to be the activated form of the transcription factor [16].…”