Gut Microbiota Species Can Provoke both Inflammatory and Tolerogenic Immune Responses in Human Dendritic Cells Mediated by Retinoic Acid Receptor Alpha Ligation.
Gut Microbiota Species Can Provoke both Inflammatory and Tolerogenic Immune Responses in Human Dendritic Cells Mediated by Retinoic Acid Receptor Alpha Ligation.
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DOI：
10.3389/fimmu.2017.00427
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发表时间：
2017
影响因子：
7.3
通讯作者：
Rajnavolgyi E
中科院分区：
文献类型：
--
作者：
Bene K;Varga Z;Petrov VO;Boyko N;Rajnavolgyi E
树突状细胞被认为是粘膜和全身免疫应答的主要协调者，因此在形成效应细胞应答的结果中起决定性作用。然而，在具有独特免疫调节特性的大肠杆菌存在下，原代人单核细胞来源的DC（moDC）群体如何驱动辅助性T（Th）细胞的极化仍然未被揭示。此外，肠道微生物群的个体成员具有调节免疫应答结果的潜力，并通过激活视黄酸受体α（RARα）来形成分化moDC的免疫原性。在这里，我们报告说，moDCs能够介导强大的Th1和Th17反应后，大肠杆菌Schaedler或摩根氏菌的刺激，而益生菌枯草芽孢杆菌菌株限制了这种效果。此外，生理浓度的全反式视黄酸（ATRA）能够重新编程moDC的分化，导致主转录因子RARα和干扰素调节因子4的基因表达谱改变，并伴随地将细胞表面的CD 1蛋白以及粘膜相关的CD 103整合素的表达水平调节到不同的方向。还证明了ATRA调节的moDC表现出增强的促炎细胞因子分泌，同时降低了它们的共刺激和抗原呈递能力，从而降低了Th1并呈现针对测试的微生物群菌株的不可检测的Th17型应答。重要的是，这些调节回路可以通过选择性抑制RARα功能来阻止。这些结果共同表明，所选的大肠杆菌菌株能够通过moDC驱动强烈的效应免疫应答，而在ATRA存在下，它们以RARα依赖性方式支持致耐受性和炎性moDC的发展。
Dendritic cells are considered as the main coordinators of both mucosal and systemic immune responses, thus playing a determining role in shaping the outcome of effector cell responses. However, it is still uncovered how primary human monocyte-derived DC (moDC) populations drive the polarization of helper T (Th) cells in the presence of commensal bacteria harboring unique immunomodulatory properties. Furthermore, the individual members of the gut microbiota have the potential to modulate the outcome of immune responses and shape the immunogenicity of differentiating moDCs via the activation of retinoic acid receptor alpha (RARα). Here, we report that moDCs are able to mediate robust Th1 and Th17 responses upon stimulation by Escherichia coli Schaedler or Morganella morganii, while the probiotic Bacillus subtilis strain limits this effect. Moreover, physiological concentrations of all-trans retinoic acid (ATRA) are able to re-program the differentiation of moDCs resulting in altered gene expression profiles of the master transcription factors RARα and interferon regulatory factor 4, and concomitantly regulate the cell surface expression levels of CD1 proteins and also the mucosa-associated CD103 integrin to different directions. It was also demonstrated that the ATRA-conditioned moDCs exhibited enhanced pro-inflammatory cytokine secretion while reduced their co-stimulatory and antigen-presenting capacity thus reducing Th1 and presenting undetectable Th17 type responses against the tested microbiota strains. Importantly, these regulatory circuits could be prevented by the selective inhibition of RARα functionality. These results altogether demonstrate that selected commensal bacterial strains are able to drive strong effector immune responses by moDCs, while in the presence of ATRA, they support the development of both tolerogenic and inflammatory moDC in a RARα-dependent manner.