Encephalitozoon intestinalis Inhibits Dendritic Cell Differentiation through an IL-6-Dependent Mechanism.
Encephalitozoon intestinalis Inhibits Dendritic Cell Differentiation through an IL-6-Dependent Mechanism.
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DOI：
10.3389/fcimb.2016.00004
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发表时间：
2016
影响因子：
5.7
通讯作者：
Ramirez-Pineda JR
中科院分区：
文献类型：
--
作者：
Bernal CE;Zorro MM;Sierra J;Gilchrist K;Botero JH;Baena A;Ramirez-Pineda JR
微孢子虫是一组细胞内病原体，分别在免疫功能正常和免疫功能低下的个体中引起自限性和严重疾病。由IL-12、IFNγ、CD 4+和CD 8 + T细胞介导的细胞1型适应性应答已被证明是宿主抵抗所必需的，而树突状细胞（DC）在引发抗微孢子虫免疫中起关键作用。我们研究了体外DC和DC前体/祖细胞对人类微孢子虫病的常见病原体脑孢子虫（Ei）感染的反应。Ei暴露的DC培养物上调MHC II类和共刺激分子CD 86和CD 40的表面表达，只有当使用高负荷的孢子。在这些培养物中还观察到IL-6的剧烈分泌，但不观察到IL-1β或IL-12 p70的剧烈分泌。Ei暴露的DC培养物由未成熟的感染和成熟的旁观者DC组成，如通过MHC II类和共刺激分子表达所评估的，表明细胞内Ei孢子在DC中传递抑制信号。此外，Ei选择性地抑制LPS刺激的DC分泌IL-12 p70。尽管Ei暴露的DC在DC-CD 4 + T细胞共培养物中促进同种异体幼稚T细胞增殖以及IL-2和IFNγ分泌，但与旁观者或感染的DC分离的共培养物分别显示刺激或抑制IFNγ分泌。当DC前体/祖细胞暴露于Ei孢子时，观察到DC分化的显著抑制，而不使发育向与髓源性抑制细胞表型或功能相容的细胞转移。中和实验表明，这种抑制作用是IL-6依赖性的。总之，这项研究揭示了一种新的潜在机制，免疫逃逸的微孢子虫寄生虫通过调制DC分化和成熟。
Microsporidia are a group of intracellular pathogens causing self-limited and severe diseases in immunocompetent and immunocompromised individuals, respectively. A cellular type 1 adaptive response, mediated by IL-12, IFNγ, CD4+, and CD8+ T cells has been shown to be essential for host resistance, and dendritic cells (DC) play a key role at eliciting anti-microsporidial immunity. We investigated the in vitro response of DC and DC precursors/progenitors to infection with Encephalitozoon intestinalis (Ei), a common agent of human microsporidosis. Ei-exposed DC cultures up-regulated the surface expression of MHC class II and the costimulatory molecules CD86 and CD40, only when high loads of spores were used. A vigorous secretion of IL-6 but not of IL-1β or IL-12p70 was also observed in these cultures. Ei-exposed DC cultures consisted of immature infected and mature bystander DC, as assessed by MHC class II and costimulatory molecules expression, suggesting that intracellular Ei spores deliver inhibitory signals in DC. Moreover, Ei selectively inhibited the secretion of IL-12p70 in LPS-stimulated DC. Whereas Ei-exposed DC promoted allogeneic naïve T cell proliferation and IL-2 and IFNγ secretion in DC-CD4+ T cell co-cultures, separated co-cultures with bystander or infected DCs showed stimulation or inhibition of IFNγ secretion, respectively. When DC precursors/progenitors were exposed to Ei spores, a significant inhibition of DC differentiation was observed without shifting the development toward cells phenotypically or functionally compatible with myeloid-derived suppressor cells. Neutralization experiments demonstrated that this inhibitory effect is IL-6-dependent. Altogether this investigation reveals a novel potential mechanism of immune escape of microsporidian parasites through the modulation of DC differentiation and maturation.