肠道蠕虫使 DC2 向调节表型发展,以对抗抗蠕虫免疫反应。

Anna T Andrusaite, Olivia J Ridgewell, Anna AM Ahlback, Holly C Webster, Hiroki Yamaguchi, Molly Peel, Annika Frede, Sarwah K Al-Khalidi, Andrew Farthing, Anna LL Heawood, Annabelle Smith, Edward W Roberts, Allan Mcl Mowat, Rick M M Maizels, Georgia Perona-Wright, Simon WF Milling
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引用次数: 0

摘要

肠道免疫系统在保护所需的主动免疫和对无害抗原的耐受之间保持平衡。肠粘膜中的树突状细胞(DC)是这些免疫调节事件中适应性臂的关键。树突状细胞对组织中的抗原进行采样,然后迁移到引流淋巴结,为 T 细胞提供能量,T 细胞再作为效应细胞或调节细胞迁移回组织。肠道 DC 具有高度异质性,目前仍不清楚究竟是哪个亚群诱导了不同类型的免疫反应,也不清楚其中涉及哪些信号分子和细胞机制。在这里,我们利用小鼠感染多角体螺旋体(Hpb)对这些问题进行了研究,Hpb 是一种独特的适合剖析肠道调节回路的模型,它在驱动 2 型保护性免疫的同时抑制免疫反应的其他方面。在这里,我们首次描述了 Hpb 感染期间肠道 DC 的特征。在整个感染过程中,我们观察到肠道直流电种群的动态变化,这种变化与表型和功能的改变有关。特别是,感染 Hpb 后,CD103+ DC2 的数量增加,它们在感染过程中保持了驱动 Tregs 的强大能力,与 CD103- DC2 不同的是,它们诱导促炎免疫反应的能力降低了。此外,转录分析表明,TGFb 信号可能是导致所观察到的某些变化的原因。这一点在体外得到了证实,补充 TGFb 或 Hpb 产生的 TGFb;模拟物(TGM)复制了体内 DCs 的免疫调节效应。总之,这些结果从机理上解释了 Hpb 等蠕虫如何通过改变当地 DC 的分化和功能来调节宿主的免疫反应。此外,我们的研究还为从分子和细胞水平理解肠道免疫平衡提供了基础。因此,这项工作填补了我们在基础生物学知识方面的一个重要空白,强调了适应性免疫反应中心回路中DC在促炎和抗炎免疫反应之间的决定作用。
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Intestinal helminth skews DC2 development towards regulatory phenotype to counter the anti-helminth immune response.
The intestinal immune system maintains a balance between active immunity needed for protection and tolerance towards harmless antigens. Dendritic cells (DCs) found in the intestinal mucosa are key to the adaptive arm of these immunoregulatory events. DCs sample antigens in the tissue and then migrate to the draining lymph nodes, where they prime the T cells that then migrate back to the tissue as effector or regulatory cells. Intestinal DC are highly heterogeneous, and it remains unclear exactly which subsets induces the different kinds of immune response, or what signalling molecules and cellular mechanisms are involved. Here, we have studied these issues using Heligmosomoides polygyrus bakeri (Hpb) infection in mice, a model which is uniquely suited to dissecting this regulatory circuit in the gut, where it drives type 2 protective immunity at the same time as inhibiting other aspects of the immune response. Here, we characterise intestinal DC during Hpb infection for the first time. We observed a dynamical change of intestinal DC populations throughout the course of infection that correlated with altered phenotype and function. In particular, Hpb infection saw a rise in a population of CD103+ DC2 that retained a potent ability to drive Tregs during the infection and unlike CD103- DC2, had a reduced ability to induce pro-inflammatory immune response. Furthermore, transcriptional analysis revealed that TGFb signalling may be responsible for some of the changes observed. This was confirmed in vitro, where supplementation TGFb or Hpb-produced TGFb; mimic (TGM) replicated the immunomodulatory effects seen in DCs in vivo. Together, these results present a mechanistic explanation of how helminths such as Hpb may modulate host immune responses by altering the differentiation and function of local DCs. Furthermore, our work provides the basis for understanding immune homeostasis in the intestine at the molecular and cellular levels. Thus, this work fills out a crucial gap in our knowledge of basic biology underlining the DC decision between pro- and anti-inflammatory immune response in the central circuit of adaptive immune response.
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