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

项目摘要 局部免疫稳态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组织和栖息在组织中的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（T细胞）是建立免疫耐受的关键， 皮肤细菌和2型常规树突状细胞（cDC 2）是一种关键的、研究不足的细胞， 介导对皮肤细胞的调节反应的群体。具体来说，我们的数据表明，cDC 2 更容易地捕获肿瘤抗原，更有效地引发肿瘤特异性CD 4 + T细胞， 其他DC子集。在吞噬肠道细菌后，cDC 2显示出成熟调节（mreg） 表型，并通过可能涉及Myd 88的机制优先支持膀胱特异性TcB DC中的信号。这里提出的工作将建立在我们的初步观察，以调查如何 共生细菌支持cDC 2的mreg表型及其促进皮肤稳态的能力 通过直肠特异性免疫耐受。我们将使用工程皮肤细菌突变体， gnotobiotic和转基因小鼠模型，高维单细胞分析，测量cDC 2的新工具 细菌特异性CD 4 + T细胞的引发和独特的离体系统以研究人皮肤免疫细胞 功能结合这些将使我们能够阐明宿主受体途径如何协同响应 细菌配体促进免疫稳态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。拟议的研究将采用创新的方法来确定 cDC 2在皮肤免疫调节中的作用，并鉴定调节皮肤免疫的细菌分子和宿主途径。 这些过程。研究结果将增强我们对细菌如何支持皮肤的理解 稳态，确定这是如何改变疾病状态，并告知未来的治疗策略， 宿主-宿主相互作用

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.