Trypanosoma cruzi trans-sialidase prevents elicitation of Th1 cell response via interleukin 10 and downregulates Th1 effector cells.
Trypanosoma cruzi trans-sialidase prevents elicitation of Th1 cell response via interleukin 10 and downregulates Th1 effector cells.
复制标题
克氏锥虫转唾液酸酶可防止通过白细胞介素 10 引发 Th1 细胞反应并下调 Th1 效应细胞。
DOI：
10.1128/iai.00031-15
复制
发表时间：
2015
影响因子：
3.1
通讯作者：
Campetella,Oscar
中科院分区：
文献类型：
--
作者：
RuizDíaz,Pablo;Mucci,Juan;Meira,MaríaAna;Bogliotti,Yanina;Musikant,Daniel;Leguizamón,MaríaSusana;Campetella,Oscar
查加斯病的病原体克氏锥虫的转唾液酸酶（TS）是释放到血液中的毒力因子，可诱导免疫系统的强烈改变。在这里，我们报告，酶活性TS（aTS）和它的凝集素样亚型（iTS）干扰CD 4 T细胞的生理，诱导下调Th 1细胞功能和体内细胞扩增。通过使用卵清蛋白特异性DO11.10细胞作为发展Th 1表型的克隆的示踪剂，我们发现感染诱导了大量的γ干扰素（IFN-γ），但体内白细胞介素2（IL-2）水平较低，IL-4的产生增加，与混合的T辅助反应一致。与Th 2表型相关的细胞因子的产生通过抗TS中和抗体的被动转移来防止。TS还减少了T细胞受体信号传导，如通过Zap-70磷酸化测定的。TS还减少IL-2和IFN-γ分泌，伴随着IL-4产生的增加，然后CD 4 T细胞对Th 2表型的反应失衡。这种效应通过使用抗IL-10中和抗体或IL-10−/−抗原呈递细胞来阻止，支持这种调节途径的颠覆。作为支持，TS在与CD 4 T细胞相互作用期间刺激抗原递呈细胞分泌IL-10。当极化细胞在TS存在下刺激时，Th 1细胞中IL-2和IFN-γ的分泌强烈下调，而Th 2细胞中IL-2的产生上调。虽然Th 1应答与宿主存活相关，但它可同时诱导对感染组织的广泛损伤。因此，通过延迟Th 1应答的激发并限制其效应特性，TS抑制细胞应答，支持T. cruzi定殖和持久性，同时有利于宿主生存。
Thetrans-sialidases (TSs) from Trypanosoma cruzi, the agent of Chagas disease, are virulence factors shed to the bloodstream that induce strong alterations in the immune system. Here, we report that both enzymatically active TS (aTS) and its lectinlike isoform (iTS) disturb CD4 T cell physiology, inducing downregulation of Th1 cell functionality andin vivocell expansion. By using ovalbumin-specific DO11.10 cells as tracers of clones developing the Th1 phenotype, we found that the infection induced significant amounts of gamma interferon (IFN-γ) but low levels of interleukin 2 (IL-2) and increased IL-4 productionin vivo, in agreement with a mixed T helper response. The production of cytokines associated with the Th2 phenotype was prevented by passive transfer of anti-TS neutralizing antibodies. TSs also reduced the T cell receptor signaling as assayed by Zap-70 phosphorylation. TSs also reduced IL-2 and IFN-γ secretion, with a concomitant increase in IL-4 production and then an unbalancing of the CD4 T cell response toward the Th2 phenotype. This effect was prevented by using anti-IL-10 neutralizing antibodies or IL-10−/−antigen-presenting cells, supporting the subversion of this regulatory pathway. In support, TSs stimulated IL-10 secretion by antigen-presenting cells during their interaction with CD4 T cells. When polarized cells were stimulated in the presence of TSs, the secretion of IL-2 and IFN-γ was strongly downregulated in Th1 cells, while IL-2 production was upregulated in Th2 cells. Although the Th1 response is associated with host survival, it may simultaneously induce extensive damage to infected tissues. Thus, by delaying the elicitation of the Th1 response and limiting its effector properties, TSs restrain the cell response, supporting T. cruzi colonization and persistence while favoring host survival.