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

皮肤微生物免疫串扰中调节性骨髓细胞的功能剖析

基本信息

批准号：
10337996
负责人：
Tiffany Crawford Scharschmidt
金额：
$ 59.86万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-07 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10337996
关键词：
Acne Animal Model Antigen-Presenting Cells Antigens Atopic Dermatitis Bacteria Behavior Biopsy CD4 Positive T Lymphocytes Cell Communication Cell physiology Cells Cellular biology Consequentialism Cues Cutaneous Data Dendritic Cells Detection Disease Dissection Engineered skin Functional disorder Future Gnotobiotic Goals Hidradenitis Suppurativa Homeostasis Human Immune Immune Tolerance Inflammatory Left Ligands Maintenance Measures Mediating Microbe Mus Myeloid Cells Nature Neonatal Pathologic Pathway interactions Phagocytosis Phenotype Population Positioning Attribute Process Regulatory T-Lymphocyte Role Shapes Signal Transduction Site Skin Surface Symbiosis System T-Lymphocyte TLR2 gene Testing Therapeutic Tissues Transgenic Animals Transgenic Mice Work cell type chronic inflammatory skin commensal bacteria commensal microbes dimensional analysis germ free condition high dimensionality human tissue immunoregulation innate immune pathways innovation microbial community microbiome microbiota mouse model mutant novel novel therapeutic intervention prevent receptor receptor binding response single cell analysis skin disorder skin microbiome tool uptake

项目摘要

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.

项目摘要局部免疫稳态的建立和维护对于身体的完整性和功能至关重要屏障组织。此过程涉及组织与居住的共生微生物之间的伙伴关系这些站点。我们已经证明了调节性T细胞（TREG）是建立免疫耐受性的关键皮肤共生细菌和2型的常规树突状细胞（CDC2）是关键的，研究的介导对皮肤份额的调节反应的人群。具体而言，我们的数据表明CDC2S 比相比其他DC子集。吞噬吞噬细胞后，CDC2显示出成熟的调节（MREG）表型和优先通过可能涉及MyD88的机制支持共生特异性的Treg DC中的信号。这里提出的工作将基于我们的初步观察，以调查如何共生细菌支持CDC2的MREG表型及其促进皮肤稳态的能力通过共生特异性的免疫耐受性。我们将使用工程的皮肤共生细菌突变体， gnotobiotic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细胞的启动和独特的离体系统研究人类皮肤免疫细胞功能。结合这些将使我们能够阐明宿主受体途径如何合作响应细菌配体可促进免疫稳态，这些反应在皮肤病中有什么不同，特别是Hidradenenitis purativa。拟议的研究将使用创新方法来定义皮肤免疫调节中的CDC2并鉴定细菌分子和宿主途径这些过程。结果将增强我们对细菌伴侣如何支持皮肤的理解稳态，确定疾病状态中如何改变这种情况，并为未来的治疗策略提供针对目标主机互动。