Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1
Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1
复制标题
DOI：
10.1038/nature05673
复制
发表时间：
2007-04-05
期刊：
影响因子：
64.8
通讯作者：
Sakaguchi, Shimon
中科院分区：
文献类型：
--
作者：
Ono, Masahiro;Yaguchi, Hiroko;Sakaguchi, Shimon
天然产生的CD 25（+）CD 4（+）调节性T细胞（T-R细胞）通过抑制异常或过度的免疫应答（如自身免疫性疾病和过敏）参与维持免疫自身耐受和免疫稳态（1-3）。T-R细胞特异性表达转录因子Foxp 3，这是T-R细胞发育和功能的关键调节因子。Foxp 3在常规T细胞中的异位表达确实足以赋予抑制活性，抑制细胞因子如白介素-2（IL-2）和干扰素-γ（IFN-γ）的产生，并上调T-R细胞相关分子如CD 25、细胞毒性T淋巴细胞相关抗原-4和糖皮质激素诱导的TNF受体家族相关蛋白（4-7）。然而，Foxp 3控制这些分子事件的方法尚未得到解释。在这里，我们发现，转录因子AML 1（急性髓性白血病1）/Runx 1（Runt相关转录因子1），这是至关重要的正常造血，包括胸腺T细胞发育（8-11），激活IL-2和IFN-γ基因表达在传统的CD 4（+）T细胞通过结合到其各自的启动子。在天然T-R细胞中，Foxp 3与AML 1发生物理相互作用。几条证据支持这样一种模型，其中相互作用抑制IL-2和IFN-γ的产生，上调T-R细胞相关分子，并发挥抑制活性。通过Foxp 3和AML 1之间的相互作用对T-R细胞功能的这种转录控制可用于控制生理和病理T细胞介导的免疫应答。
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.