多发性硬化症、糖尿病和关节炎等疾病都是自体免疫疾病，这是由于一种称为调节性T细胞的白血球发生问题所致。
在之前的研究中，科学家们发现调节性T细胞受到一种名为Foxp3的主调控基因的控制。主调控基因与单个基因结合，进而控制它们的活动进而影响细胞的行为。实际上，如果 Foxp3停止工作，人体就无法生产调节性T细胞。在这种情况下，普通T细胞就会破坏人体器官，引起各种自免疫性疾病。而直到现在，科学家们对Foxp3 到底如何控制调节性T细胞所知甚少，因为他们对那些直接受到Foxp3影响的基因几乎一无所知。
根据一篇发表于Proceedings of the National Academy of Sciences的新研究中，宾州大学医学院的研究人员发现如何修改作用于FOXP3 蛋白质的酵素，并使调节性T细胞能更顺利地发挥其功能。
这些研究结果对于自体免疫疾病的治疗意义重大。FOXP3蛋白质可以作用于一套复杂的酵素：组蛋白去乙酰化酶(HDACs)。这些酵素使FOXP3 蛋白质与另外一套称为组蛋白乙酰转移酶(HATs)的酵素产生关连性。
研究人员发现，当HATs启动或当HDACs关闭时，免疫调节细胞的运作更顺利且更长久。如果FOXP3 蛋白质的功能被关闭，会导致自体免疫疾病。因此研究人员认为可以针对这二种酵素研发药物，以控制免疫调节细胞的运作，进而治疗自体免疫疾病。
(资料来源 : biocompare)
FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression
Bin Li, Arabinda Samanta, Xiaomin Song, Kathryn T. Iacono, Kathryn Bembas, Ran Tao, Samik Basu, James L. Riley, Wayne W. Hancock, Yuan Shen, Sandra J. Saouaf, and Mark I. Greene*
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-6082
Communicated by Peter C. Nowell, University of Pennsylvania School of Medicine, Philadelphia, PA, January 20, 2007 (received for review November 21, 2006)
Abstract
The forkhead family protein FOXP3 acts as a repressor of transcription and is both an essential and sufficient regulator of the development and function of regulatory T cells. The molecular mechanism by which FOXP3-mediated transcriptional repression occurs remains unclear. Here, we report that transcriptional repression by FOXP3 involves a histone acetyltransferase–deacetylase complex that includes histone acetyltransferase TIP60 (Tat-interactive protein, 60 kDa) and class II histone deacetylases HDAC7 and HDAC9. The N-terminal 106–190 aa of FOXP3 are required for TIP60–FOXP3, HDAC7–FOXP3 association, as well as for the transcriptional repression of FOXP3 via its forkhead domain. FOXP3 can be acetylated in primary human regulatory T cells, and TIP60 promotes FOXP3 acetylation in vivo. Overexpression of TIP60 but not its histone acetyltransferase-deficient mutant promotes, whereas knockdown of endogenous TIP60 relieved, FOXP3-mediated transcriptional repression. A minimum FOXP3 ensemble containing native TIP60 and HDAC7 is necessary for IL-2 production regulation in T cells. Moreover, FOXP3 association with HDAC9 is antagonized by T cell stimulation and can be restored by the protein deacetylation inhibitor trichostatin A, indicating a complex dynamic aspect of T suppressor cell regulation. These findings identify a previously uncharacterized complex-based mechanism by which FOXP3 actively mediates transcriptional repression.
A central theme that has emerged over the last 25 years is that a process of self-regulation of the immune response occurs to limit self-reactivity. Biochemical details of how the immune system distinguishes and regulates self and non-self remain to be fully documented (1). A recently characterized CD4+CD25+ regulatory T cell subset expresses the Foxp3 transcription factor. As a transcriptional repressor of cytokine gene expression (2), Foxp3 was subsequently identified as an essential and sufficient regulator of natural regulatory T cell development and function (3–5).
Mammalian transcriptional repressors can execute their function by either passive or active mechanisms (6, 7). FOXP3 may, for example, function as a passive transcriptional repressor in the case of its association with NFAT and NF-B (8, 9). In this study, we explore the role of FOXP3 as an active transcriptional repressor by revealing the dynamic FOXP3 ensemble formation with a specific histone acetyltransferase (HAT) and certain class II histone deacetylases (HDACs) in expanded human CD4+CD25+ regulatory T cells (10, 11).
Histone acetylation and histone deacetylation affect chromatin remodeling during T cell development and differentiation (12, 13). HAT and HDAC abnormalities have been associated with leukemia (14, 15), diabetes (16) and other diseases of the immune system (17–19). The linkage of HAT and HDAC as components of a single complex permits dynamic responsiveness to extracellular stimulation (18, 20). The HAT TIP60 (Tat-interactive protein, 60 kDa), originally isolated as an HIV-1 TAT-interactive protein (21), functions as either a transcriptional coactivator or transcriptional corepressor (22, 23). Activated TIP60 can exert its acetyltransferase activity on a variety of proteins, including histone H2A, H3, and H4 (21), protein kinase ATM (24), and transcription factors such as c-myc (25) and p53 (26, 27). TIP60 also functions as a transcriptional corepressor of STAT3 in part through the recruitment of HDAC7 (28, 29).
Class II HDAC subfamily members include HDAC4, HDAC5, HDAC7, HDAC9, and HDAC10, all of which contain an N-terminal 17-aa MEF2D-binding motif, but only HDAC7 and HDAC9 are highly expressed in CD4+ T cells (30, 31). HDAC7 is highly expressed in CD4+CD8+ double positive T cells and regulates negative selection in the thymus by means of inhibition of Nur77 transcription through the specific recruitment of MEF2D to its binding site on the Nur77 promoter (30). HDAC9 expression is notably higher in mouse Foxp3gfp+CD4+ T cells than Foxp3gfp–CD4+ T cells (31).
Here, we provide evidence that FOXP3 actively represses transcription through its association with HAT TIP60 and HDAC7 and HDAC9 in vivo. We identified the N-terminal 106- to 190-aa proline-rich region of FOXP3, which has little similarity with other FOXP subfamily members, as a critical region for FOXP3 forkhead domain-mediated transcriptional repression, dependent on its dynamic association with TIP60 and HDAC7. Moreover, we demonstrate that FOXP3 is acetylated in primary human regulatory T cells and show that this process is promoted by TIP60. Whereas overexpression of TIP60, but not its HAT-deficient mutant, promotes FOXP3-mediated transcriptional repression, endogenous knockdown of TIP60 relieves this repression.
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