Foxp3⁺ regulatory T cells delay expulsion of intestinal nematodes by suppression of IL-9-driven mast cell activation in BALB/c but not in C57BL/6 mice.
Foxp3⁺ regulatory T cells delay expulsion of intestinal nematodes by suppression of IL-9-driven mast cell activation in BALB/c but not in C57BL/6 mice.
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DOI：
10.1371/journal.ppat.1003913
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发表时间：
2014-02
期刊：
影响因子：
6.7
通讯作者：
Breloer M
中科院分区：
文献类型：
--
作者：
Blankenhaus B;Reitz M;Brenz Y;Eschbach ML;Hartmann W;Haben I;Sparwasser T;Huehn J;Kühl A;Feyerabend TB;Rodewald HR;Breloer M
越来越多的证据表明，IL-9 介导的免疫在控制肠道线虫感染中发挥着重要作用。在此，我们报告了 Foxp3+ 调节性 T 细胞 (Treg) 对线虫诱导的 BALB/c 和 C57BL/6 小鼠逃避 IL-9 介导的免疫的不同影响。鼠类圆线虫感染诱导 Treg 扩增，两种菌株具有相似的动力学和表型。引人注目的是，Treg 消除选择性地减少了 BALB/c 小鼠的寄生虫负担，但没有减少 C57BL/6 小鼠的寄生虫负担。 Treg 功能在两种品系中都很明显，因为 Treg 耗竭在 BALB/c 和 C57BL/6 小鼠中以相同程度增加了线虫特异性体液和细胞 Th2 反应。 Treg 耗尽的 BALB/c 小鼠抵抗力的改善伴随着 IL-9 产量的增加和肥大细胞脱颗粒的加速。相比之下，C57BL/6 小鼠中 IL-9 的产生并没有显着升高，并且肥大细胞脱颗粒的动力学不受 Treg 消耗的影响。通过体内中和，我们证明在感染的第一天，IL-9 产生的增加导致肥大细胞脱颗粒加速，并从 Treg 耗尽的 BALB/c 小鼠的小肠中快速排出鼠链球菌成虫。在遗传性肥大细胞缺陷 (Cpa3-Cre) BALB/c 小鼠中，Treg 缺失仍导致 IL-9 产量增加，但对鼠链球菌感染的抵抗力丧失，表明 IL-9 驱动的肥大细胞激活介导 Treg 缺失的 BALB/c 小鼠中鼠链球菌的加速排出。这种 IL-9 驱动的肥大细胞脱颗粒是 BALB/c 和 C57BL/6 小鼠中鼠链球菌排出的核心机制，因为在两种品系中，在 Treg 存在的情况下，IL-9 注射减少，而 IL-9 中和增加了寄生虫负担。因此，我们的结果表明，在 BALB/c 小鼠中，Foxp3+ Treg 以非冗余方式抑制了大鼠沙门氏菌感染期间随后肥大细胞脱颗粒的足够 IL-9 产生，而额外的调节途径在 Treg 耗尽的 C57BL/6 小鼠中起作用。寄生蠕虫是大型多细胞生物，尽管暴露于宿主的免疫系统，但仍能完成其生命周期。为了避免被驱逐，寄生虫会主动抑制宿主的免疫反应。在这里，我们发现致病性线虫鼠类圆线虫会诱导调节性免疫细胞的特殊亚群——调节性 T 细胞 (Treg) 的扩增，从而抵消效应 T 细胞的功能。在两种不同的小鼠品系 BALB/c 和 C57BL/6 中，Treg 以相似的动力学扩张并抑制线虫特异性免疫反应的大部分特征。这种免疫反应的一个核心因素，即 IL-9 驱动的肥大细胞快速脱颗粒，在 BALB/c 小鼠中被寄生虫诱导的 Treg 非冗余地抑制。因此，Treg 细胞的耗竭增加了 IL-9 的产生，加速了肥大细胞脱粒，并导致 BALB/c 小鼠中鼠链球菌快速排出。在缺乏 Treg 的情况下，感染鼠链球菌的 C57BL/6 小鼠仍表现出较低的 IL-9 产量和延迟的肥大细胞脱颗粒。因此，S.ratti能够在Treg耗尽的C57BL/6小鼠中完成其生命周期。这项研究表明，寄生虫通过过度激活宿主免疫系统的调节元件（如 Treg）来延迟其排出。免疫逃避过程中各个调控元件的重要性取决于它们在宿主内的冗余程度，而该冗余程度在不同的遗传背景中是可变的。
Accumulating evidence suggests that IL-9-mediated immunity plays a fundamental role in control of intestinal nematode infection. Here we report a different impact of Foxp3+ regulatory T cells (Treg) in nematode-induced evasion of IL-9-mediated immunity in BALB/c and C57BL/6 mice. Infection with Strongyloides ratti induced Treg expansion with similar kinetics and phenotype in both strains. Strikingly, Treg depletion reduced parasite burden selectively in BALB/c but not in C57BL/6 mice. Treg function was apparent in both strains as Treg depletion increased nematode-specific humoral and cellular Th2 response in BALB/c and C57BL/6 mice to the same extent. Improved resistance in Treg-depleted BALB/c mice was accompanied by increased production of IL-9 and accelerated degranulation of mast cells. In contrast, IL-9 production was not significantly elevated and kinetics of mast cell degranulation were unaffected by Treg depletion in C57BL/6 mice. By in vivo neutralization, we demonstrate that increased IL-9 production during the first days of infection caused accelerated mast cell degranulation and rapid expulsion of S. ratti adults from the small intestine of Treg-depleted BALB/c mice. In genetically mast cell-deficient (Cpa3-Cre) BALB/c mice, Treg depletion still resulted in increased IL-9 production but resistance to S. ratti infection was lost, suggesting that IL-9-driven mast cell activation mediated accelerated expulsion of S. ratti in Treg-depleted BALB/c mice. This IL-9-driven mast cell degranulation is a central mechanism of S. ratti expulsion in both, BALB/c and C57BL/6 mice, because IL-9 injection reduced and IL-9 neutralization increased parasite burden in the presence of Treg in both strains. Therefore our results suggest that Foxp3+ Treg suppress sufficient IL-9 production for subsequent mast cell degranulation during S. ratti infection in a non-redundant manner in BALB/c mice, whereas additional regulatory pathways are functional in Treg-depleted C57BL/6 mice. Parasitic worms are large multicellular organisms that manage completion of their life cycles despite exposure to their host's immune system. To avoid expulsion, parasitic worms actively suppress their host's immune response. Here we show that the pathogenic nematode Strongyloides ratti induces the expansion of a specialized subset of regulatory immune cells, regulatory T cells (Treg), that counteract effector T cell function. Treg expanded with similar kinetics and suppressed most features of the nematode-specific immune response in two different mouse strains, BALB/c and C57BL/6. One central factor of this immune response i.e. IL-9-driven rapid degranulation of mast cells, was suppressed by parasite-induced Treg in BALB/c mice non-redundantly. Consequently, Treg depletion elevated IL-9 production, accelerated mast cell degranulation and led to rapid expulsion of S. ratti in BALB/c mice. S. ratti-infected C57BL/6 mice still displayed low IL-9 production and delayed mast cell degranulation in the absence of Treg. Thus S. ratti was able to complete its life cycle in Treg-depleted C57BL/6 mice. This study shows that parasitic worms delay their expulsion by over-activating regulatory elements of their host's immune system such as Treg. The importance of individual regulatory elements during immune evasion depends on their degree of redundancy within the host that is variable in different genetic backgrounds.
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DOI：
10.1084/jem.20101074
发表时间：
2010-10-25
期刊：
The Journal of experimental medicine
影响因子：
--
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
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
影响因子：
5.4
作者：
Faulkner, H;Humphreys, N;Grencis, R
通讯作者：
Grencis, R
影响因子：
2.1
作者：
Brigandi, RA;Rotman, HL;Abraham, D
通讯作者：
Abraham, D
影响因子：
32.4
作者：
Gri G;Piconese S;Frossi B;Manfroi V;Merluzzi S;Tripodo C;Viola A;Odom S;Rivera J;Colombo MP;Pucillo CE
通讯作者：
Pucillo CE