Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-β pathway.
Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-β pathway.
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DOI：
10.1084/jem.20101074
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发表时间：
2010-10-25
期刊：
影响因子：
--
通讯作者：
Maizels RM
中科院分区：
文献类型：
--
作者：
Grainger JR;Smith KA;Hewitson JP;McSorley HJ;Harcus Y;Filbey KJ;Finney CA;Greenwood EJ;Knox DP;Wilson MS;Belkaid Y;Rudensky AY;Maizels RM
肠道寄生虫H.多脑回分泌诱导调节性T细胞的TGF-β样分子，从而抑制宿主的抗寄生虫效应T细胞应答。表达Foxp 3的调节性T（T reg）细胞与慢性感染期间寄生虫驱动的宿主免疫抑制有关。我们讨论了寄生虫是否可以直接诱导T reg细胞。在感染肠道蠕虫Heligmosomoides polygyrus的小鼠中，Foxp 3的表达在初始Foxp 3 − T细胞中受到刺激。在体外，寄生虫分泌的蛋白质（称为H。多脑回排泄分泌抗原[HES]）诱导Foxp 3-绿色荧光蛋白报告小鼠荧光分选的Foxp 3 −脾细胞中Foxp 3的从头表达。HES诱导的T reg细胞抑制体外效应细胞增殖和体内过敏性气道炎症。HES连接转化生长因子（TGF）β受体并促进Smad 2/3磷酸化。在显性阴性TGF-βRII细胞中，HES对Foxp 3的诱导作用丧失，并被TGF-β信号传导抑制剂SB 431542消除。这种抑制剂也降低了H.感染多脑回的小鼠。HES在IL-6存在下诱导IL-17，但在任何条件下均不促进Th 1或Th 2发育。重要的是，哺乳动物TGF-β的抗体不识别HES，而抑制HES的抗血清不影响TGF-β。Foxp 3也被Teladorsagia circumcincta的分泌产物诱导，Teladorsagia circumcincta是一种广泛存在于反刍动物中的相关线虫。因此，我们已经确定了一种新的途径，通过该途径，蠕虫寄生虫可以刺激T reg细胞，这可能是寄生虫与宿主的免疫关系的关键部分。
The intestinal parasite H. polygyrus secretes a TGF-β–like molecule that induces regulatory T cells, thus suppressing anti-parasitic effector T cell responses by the host. Foxp3-expressing regulatory T (T reg) cells have been implicated in parasite-driven inhibition of host immunity during chronic infection. We addressed whether parasites can directly induce T reg cells. Foxp3 expression was stimulated in naive Foxp3− T cells in mice infected with the intestinal helminth Heligmosomoides polygyrus. In vitro, parasite-secreted proteins (termed H. polygyrus excretory-secretory antigen [HES]) induced de novo Foxp3 expression in fluorescence-sorted Foxp3− splenocytes from Foxp3–green fluorescent protein reporter mice. HES-induced T reg cells suppressed both in vitro effector cell proliferation and in vivo allergic airway inflammation. HES ligated the transforming growth factor (TGF) β receptor and promoted Smad2/3 phosphorylation. Foxp3 induction by HES was lost in dominant-negative TGF-βRII cells and was abolished by the TGF-β signaling inhibitor SB431542. This inhibitor also reduced worm burdens in H. polygyrus–infected mice. HES induced IL-17 in the presence of IL-6 but did not promote Th1 or Th2 development under any conditions. Importantly, antibody to mammalian TGF-β did not recognize HES, whereas antisera that inhibited HES did not affect TGF-β. Foxp3 was also induced by secreted products of Teladorsagia circumcincta, a related nematode which is widespread in ruminant animals. We have therefore identified a novel pathway through which helminth parasites may stimulate T reg cells, which is likely to be a key part of the parasite’s immunological relationship with the host.
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影响因子：
1.5
作者：
Hewitson, James P.;Grainger, John R.;Maizels, Rick M.
通讯作者：
Maizels, Rick M.
影响因子：
32.4
作者：
Fontenot, JD;Rasmussen, JP;Rudensky, AY
通讯作者：
Rudensky, AY
影响因子：
1.9
作者：
Harcus Y;Nicoll G;Murray J;Filbey K;Gomez-Escobar N;Maizels RM
通讯作者：
Maizels RM
影响因子：
5.4
作者：
Finney, Constance A M;Taylor, Matthew D;Wilson, Mark S;Maizels, Rick M
通讯作者：
Maizels, Rick M
DOI：
10.1084/jem.20091268
发表时间：
2009-12-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Herbert DR;Yang JQ;Hogan SP;Groschwitz K;Khodoun M;Munitz A;Orekov T;Perkins C;Wang Q;Brombacher F;Urban JF Jr;Rothenberg ME;Finkelman FD
通讯作者：
Finkelman FD