Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression
Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression
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DOI：
10.1038/nature05479
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发表时间：
2007-02-15
期刊：
影响因子：
64.8
通讯作者：
Flavell, Richard A.
中科院分区：
文献类型：
--
作者：
Wan, Yisong Y.;Flavell, Richard A.
自然产生的调节性T细胞（T- r）是维持自身耐受性并发挥主动免疫抑制作用的关键细胞类型。T-R细胞的发育和功能受Foxp3控制（文献1,2），缺乏Foxp3会导致安全小鼠和IPEX（免疫失调、多内分泌病、肠病、x连锁）患者的T-R细胞缺失和大量多器官自身免疫（3,4）。一般认为，通过双重机制，Foxp3的表达作为一个开关，积极调节T-R细胞的生理；然而，新出现的证据表明Foxp3在T-R细胞中表达降低与各种免疫疾病有关（5-7）。我们假设Foxp3以一种剂量依赖的、非二元的方式调节T(R)细胞的发育和功能，Foxp3表达的降低可能导致免疫疾病。在这里，通过在T-R细胞中产生内源性Foxp3基因表达减弱的小鼠模型，我们发现Foxp3表达降低导致与安全小鼠类似的侵袭性自身免疫综合征的发展，但不影响胸腺发育、稳态扩张/维持或转化生长因子β诱导的Foxp3表达细胞的新生。Foxp3表达减弱的T细胞在体外和体内的免疫抑制活性几乎被消除，而其在体外的无能特性保持不变。这伴随着T(R)细胞“标志基因”的表达减少。值得注意的是，即使在T(H)1极化环境中，表达Foxp3减少的T细胞也优先成为T(H)2型效应细胞。这些细胞指示常规T细胞的T(H)2分化，从而导致在这些小鼠中观察到的免疫疾病。因此，Foxp3表达的降低通过破坏T-R细胞的抑制功能并将T-R细胞转化为效应细胞而引起免疫疾病；这些发现对于理解T-R细胞功能的调控和各种人类免疫疾病的病因学具有重要意义。
The naturally occurring regulatory T cell (T-R) is the pivotal cell type that maintains self-tolerance and exerts active immune suppression. The development and function of T-R cells is controlled by Foxp3 (refs 1, 2), a lack of which results in loss of T-R cells and massive multi-organ autoimmunity in scurfy mice and IPEX ( immune dysregulation, polyendocrinopathy, enteropathy, X-linked) patients(3,4). It is generally thought that, through a binary mechanism, Foxp3 expression serves as an on-and-off switch to regulate positively the physiology of T-R cells; however, emerging evidence associates decreased Foxp3 expression in T-R cells with various immune disorders(5-7). We hypothesized that Foxp3 regulates T(R)cell development and function in a dose-dependent, nonbinary manner, and that decreased Foxp3 expression can cause immune disease. Here, by generating a mouse model in which endogenous Foxp3 gene expression is attenuated in T-R cells, we show that decreased Foxp3 expression results in the development of an aggressive autoimmune syndrome similar to that of scurfy mice, but does not affect thymic development, homeostatic expansion/maintenance or transforming-growth-factor-beta-induced de novo generation of Foxp3-expressing cells. The immune-suppressive activities of T cells with attenuated Foxp3 expression were nearly abolished in vitro and in vivo, whereas their anergic properties in vitro were maintained. This was accompanied by decreased expression of T(R)cell 'signature genes'. Notably, T cells expressing decreased Foxp3 preferentially became T-helper 2 (T(H)2)-type effectors even in a T(H)1-polarizing environment. These cells instructed T(H)2 differentiation of conventional T cells, which contributed to the immune diseases observed in these mice. Thus, decreased Foxp3 expression causes immune disease by subverting the suppressive function of T-R cells and converting T-R cells into effector cells; these findings are important for understanding the regulation of T-R cell function and the aetiology of various human immune diseases.