Neonatal imprinting of tolerogenic properties in stromal cells from gut-draining lymph nodes by commensal microbiota

Foxp3+调节性T细胞（TCRs）在维持免疫稳态、自身耐受和特别是粘膜耐受中起核心作用。绝大多数Foxp3+ T细胞已经在胸腺中产生，然而，Foxp3+ T细胞的一个子集可以从外周中的常规CD4+ T细胞转化。这种Foxp3+ T细胞的外周从头产生非常有效地发生在肠引流淋巴结（LN）内，包括肠系膜LN（mLN）。使用LN移植，我们最近不仅可以证明LN基质细胞对肠道引流LN的高Treg诱导能力有重要贡献，而且肠道引流LN的这些致耐受性特性在LN基质细胞内稳定印记，并且基本上不受皮肤局部微环境或炎症扰动如胃肠道感染或慢性结肠炎的影响。重要的是，在新生儿阶段与肠道微生物群的接触可以被鉴定为负责mLN基质细胞中致耐受性特性的稳定印记的微环境因素，进一步强调了新生儿期对于全功能免疫系统发育的关键作用。我们的目的是鉴定新生期肠道微生物群在mLN基质细胞内稳定印记致耐受特性的分子机制。通过与优先计划的其他成员密切合作，我们将确定有助于这一过程的细菌物种和肠道微生物群衍生的分子介质，我们将增加我们对肠道微生物群在mLN基质细胞中表观遗传印记的分子途径的了解。我们将进一步研究在外周从头产生Foxp3+ Treg期间，肠道微生物群对Treg特异性表观遗传和转录特征形成的影响。最后，在优先计划其他成员的大力支持下，我们将研究新生儿感染的长期后果以及随后肠道微生物群组成的变化对mLN基质细胞内致耐受性的影响。作为一个整体来看，通过鉴定有助于mLN基质细胞中耐受性特性的稳定印记的细菌种类，分子介质和表观遗传机制，这个跨学科项目将进一步揭示Foxp3+ T细胞与肠道微生物群的复杂和密切联系的一层。

Foxp3+ regulatory T cells (Tregs) play a central role for the maintenance of immune homeostasis, self-tolerance and particularly mucosal tolerance. The vast majority of Foxp3+ Tregs is generated already in the thymus, however, a subset of Foxp3+ Tregs can be converted from conventional CD4+ T cells in the periphery. This peripheral de novo generation of Foxp3+ Tregs very efficiently takes place within gut-draining lymph nodes (LNs), including mesenteric LNs (mLNs). Using LN transplantations, we could recently not only demonstrate that LN stromal cells critically contribute to the high Treg-inducing capacity of gut-draining LNs, but also that these tolerogenic properties of gut-draining LNs are stably imprinted within LN stromal cells and cannot be substantially influenced either by the local microenvironment of the skin or by inflammatory perturbations such as gastrointestinal infection or chronic colitis. Importantly, contact with commensal microbiota in the neonatal phase could be identified as the microenvironmental factor being responsible for the stable imprinting of tolerogenic properties in mLN stromal cells, further emphasizing the critical role of the neonatal period for the development of a fully functional immune system.In the present project, we aim to identify the molecular mechanisms by which intestinal microbiota stably imprint tolerogenic properties within mLN stromal cells in the neonatal period. In close cooperation with other members of the Priority Programme, we will identify bacterial species and commensal microbiota-derived molecular mediators that contribute to this process, and we will increase our knowledge of the molecular pathways being epigenetically imprinted in mLN stromal cells by commensal microbiota. We will furthermore study the impact of commensal microbiota on the formation of a Treg-specific epigenetic and transcriptional signature during peripheral de novo generation of Foxp3+ Tregs. Finally, with strong support from other members of the Priority Programme, we will investigate the long-lasting consequences of neonatal infections and subsequent changes in commensal microbiota composition on the imprinting of tolerogenic properties within mLN stromal cells. Viewed as a whole, by identifying bacterial species, molecular mediators and epigenetic mechanisms that contribute to the stable imprinting of tolerogenic properties in mLN stromal cells, this interdisciplinary project will shed further light into one of the layers of the complex and intimate connection of Foxp3+ Tregs with commensal microbiota.