Regulatory dendritic cell expression of MHCII and IL-10 are jointly requisite for induction of tolerance in a murine model of OVA-asthma
Regulatory dendritic cell expression of MHCII and IL-10 are jointly requisite for induction of tolerance in a murine model of OVA-asthma
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DOI：
10.1111/all.12203
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发表时间：
2013-09-01
期刊：
影响因子：
12.4
通讯作者：
Gordon, J. R.
中科院分区：
文献类型：
--
作者：
Huang, H.;Dawicki, W.;Gordon, J. R.
背景IL-10诱导分化的树突状细胞（DC 10）通过将Th 2细胞转化为调节性T细胞（T细胞）逆转小鼠哮喘表型。DC 10表达升高水平的IL-10，但实质上降低水平的MHCII和共刺激分子，因此，这些因素之间的相互关系和致耐受性尚未明确阐明。方法我们评估了这些输入的作用，在DC 10逆转OVA相关的哮喘样疾病，通过治疗受影响的小鼠与OVA脉冲DC 10产生的野生型或IL-10-足够的MHCII-/-或CD 80/CD 86（-/-）小鼠，或用MHCII-完整的IL-10-沉默的DC 10。共刺激分子，趋化因子），但它消除了IL-10分泌和细胞诱导耐受性的能力，如通过评估气道高反应性，嗜酸性粒细胞增多和Th 2应答以回忆OVA攻击所确定的。MHCII-/-DC 10表达正常水平的IL-10，但不能诱导哮喘表型小鼠的过敏原耐受，而CD 80/CD 86（-/-）DC 10诱导的耐受减弱但不能消除。我们还评估了多种Treg细胞标志物（例如，ICOS、PD-1、GITR）对经处理小鼠肺CD 25（+）Foxp 3（+）细胞的影响。野生型DC 10处理上调每个标记物的表达，而IL-10沉默和MHCII-/-DC 10都没有这样做，并且CD 80/86（-/-）DC 10诱导中间Treg细胞活化表型。这表明DC 10和Th 2效应T细胞必须以同源的方式结合在一起，以使它们的IL-10诱导耐受性。
BackgroundAllergen-presenting dendritic cells differentiated with IL-10 (DC10) reverse the asthma phenotype in mice by converting their Th2 cells to regulatory T cells (Tregs). DC10 express elevated levels of IL-10, but substantially reduced levels of MHCII and costimulatory molecules, so the relationships between these factors with each other and tolerogenicity have not been clearly elucidated.MethodsWe assessed the roles of these inputs in DC10 reversal of OVA-associated asthma-like disease by treating affected mice with OVA-pulsed DC10 generated from wild-type or IL-10-sufficient MHCII-/- or CD80/CD86(-/-) mice, or with MHCII-intact IL-10-silenced DC10.ResultsIL-10 silencing did not discernibly affect the cells' immunobiology (e.g., costimulatory molecules, chemokines), but it eliminated IL-10 secretion and the cell's abilities to induce tolerance, as determined by assessments of airway hyper-responsiveness, eosinophilia, and Th2 responses to recall OVA challenge. MHCII-/- DC10 expressed normal levels of IL-10, but, nevertheless, were unable to induce allergen tolerance in asthma phenotype mice, while tolerance induced by CD80/CD86(-/-) DC10 was attenuated but not eliminated. We also assessed the induction of multiple Treg cell markers (e.g., ICOS, PD-1, GITR) on pulmonary CD25(+)Foxp3(+) cells in the treated mice. Wild-type DC10 treatments upregulated expression of each marker, while neither IL-10-silenced nor MHCII-/- DC10 did so, and the CD80/86(-/-) DC10 induced an intermediate Treg cell activation phenotype.ConclusionBoth IL-10 and MCHII expression by DC10 are requisite, but not sufficient for tolerance induction, suggesting that DC10 and Th2 effector T cells must be brought together in a cognate fashion in order for their IL-10 to induce tolerance.