Functional Dissection of Regulatory Myeloid Cells in Microbe-Immune Crosstalk in Skin

项目总结 局部免疫动态平衡的建立和维持对机体的完整性和功能至关重要 屏障组织。这一过程涉及到组织和共生微生物之间的伙伴关系。 这些网站。我们已经证明，调节性T细胞(Tregs)是建立免疫耐受的关键 皮肤共生细菌和2型常规树突状细胞(CDC2s)是一种关键的、未被研究的 调节对皮肤共生的调节反应的人群。具体地说，我们的数据表明CDC2 更容易捕获共生抗原，并更有效地激活共生特异性CD4+T细胞 其他DC子集。在吞噬共生菌后，cDC2表现出成熟调节(Mreg)。 表型，并通过可能涉及MyD88的机制优先支持共生特异性Tregs DC中的信令。这里提出的工作将建立在我们初步观察的基础上，以调查 共生菌支持CDC2的mreg表型及其促进皮肤动态平衡的能力 通过共生特异性免疫耐受。我们将使用基因工程皮肤共生细菌突变体， 诺生菌和转基因小鼠模型，高维单细胞分析，测量cDC2的新工具 细菌特异性CD4+T细胞和独特的体外系统的启动以研究人类皮肤免疫细胞 功能。将这些结合起来将使我们能够阐明宿主受体通路如何协同响应 细菌配体促进免疫动态平衡，以及这些反应在皮肤病中的不同方式， 特别是化脓性汗腺炎。拟议的研究将使用创新的方法来定义 CDC2在皮肤免疫调节中的作用和识别调节的细菌分子和宿主途径 这些过程。这一结果将加深我们对细菌如何配合支持皮肤的理解 动态平衡，确定这种状态在疾病状态下是如何改变的，并为未来的治疗策略提供指导 寄主-共生相互作用。

PROJECT SUMMARY Establishment and maintenance of local immune homeostasis is essential for the integrity and function of body barrier tissues. This process involves partnership between the tissue and the commensal microbes inhabiting these sites. We have demonstrated that regulatory T cells (Tregs) are key to establishing immune tolerance to skin commensal bacteria, and that type 2 conventional dendritic cells (cDC2s) are a critical, understudied population that mediate the regulatory response to skin commensals. Specifically, our data suggest that cDC2s capture commensal antigens more readily and prime commensal-specific CD4+ T cells more efficiently than other DC subsets. After phagocytosing commensal bacteria, cDC2s display a mature-regulatory (mreg) phenotype and preferentially support commensal-specific Tregs via a mechanism that may involve Myd88 signaling in DCs. The work proposed here will build on our preliminary observations to investigate how commensal bacteria support the mreg phenotype of cDC2s and their ability to promote skin homeostasis through commensal-specific immune tolerance. We will use engineered skin commensal bacteria mutants, gnotobiotic and transgenic mouse models, high dimensional single cell analyses, novel tools to measure cDC2 priming of bacteria-specific CD4+ T cells and unique ex vivo systems to study human skin immune cell function. Combining these will allow us to elucidate how host receptor pathways respond co-operatively to bacterial ligands to promote immune homeostasis and in what manner these responses differ in skin disease, specifically hidradenitis suppurativa. The proposed studies will use innovative approaches to define the role of cDC2s in cutaneous immune regulation and identify the bacterial molecules and host pathways that regulate these processes. The results will enhance our understanding of how bacteria partner to support skin homeostasis, determine how this is altered in disease states, and inform future therapeutic strategies targeting host-commensal interactions.