Gut symbiotic microbiota-derived CD1d ligands and their immunomodulatory mechanisms

肠道共生微生物衍生的 CD1d 配体及其免疫调节机制

• 批准号: 10645212
• 负责人: Sungwhan F Oh
• 金额: $ 53.01万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-14 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645212
• 关键词: Affinity; Agonist; Antigen-Presenting Cells; Antigens; Bacteroides fragilis; Biological; Cell Differentiation process; Cell physiology; Chemical Structure; Chemicals; Colitis; Colon; Colonic inflammation; Complex; Cytotoxic T-Lymphocytes; Development; Diglycerides; Disease; Disease susceptibility; Future; Human; Immune; Immune system; Immunotherapeutic agent; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Investigation; Knowledge; Life; Ligands; Lipids; MHC Class I Genes; Mediating; Microbe; Molecular; Oral Administration; Organic Synthesis; Phenotype; Population; Proliferating; Proteins; Regulation; Reporting; Signal Induction; Signal Transduction; Sphingomyelins; Structure; Structure-Activity Relationship; System; T cell response; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; T-cell receptor repertoire; TCR Activation; Variant; alpha-galactosylceramide; commensal microbes; density; host microbiota; immunoreaction; immunoregulation; in vivo; inflammatory modulation; interest; lipidomics; microbiota; microbiota metabolites; novel; pathogen; prototype; response; symbiont

Gut symbiotic microbiota–derived CD1d ligands and their immunomodulatory mechanisms PROJECT SUMMARY The symbiotic microbiota has co-evolved with the mammalian host for millennia, and the host has developed a sophisticated system for distinguishing pathogens from commensal microbes. Unlike pathogens, many of whose molecules trigger robust inflammatory and immune reactions, symbiont-derived molecular factors have been believed to be “silent,” even though they reside within the host at a very high density. However, recent studies strongly suggest that molecular factors of symbiotic origin actively contribute to host immune regulation and protection from excessive inflammation. We have previously identified and characterized a unique class of lipids (alpha-galactosylceramides) from the human gut symbiont Bacteroides fragilis that can modulate host immune development early in life. Our preliminary results show that these molecules (BfaGCs) are presented by the nonclassical MHC class I–like molecule CD1d in a structurally conserved manner similar to that documented for prototypic CD1d ligands. Of considerable interest, unlike CD1d agonists such as KRN7000, BfaGCs function as a regulator of natural killer T (NKT) cells, a specific T cell subtype restricted by the CD1d–lipid antigen complex. Synthetic BfaGC molecules can induce distinct immunomodulatory signals from NKT cells and can function as a regulator of NKT cell proliferation in the colon. Furthermore, targeted lipidomic profiling of gut symbionts has identified lipid species structurally related to BfaGCs in multiple gut symbionts, implying that gut symbionts can collectively synthesize potential NKT cell regulators. We propose an investigation of molecular immunomodulatory mechanisms that underlie the activity of gut symbiont–derived lipid ligands. We aim to determine (1) the distinct NKT population recognized by the CD1d-BfaGC complex and their immunomodulatory responses to BfaGCs, (2) the specific molecular-level interactions between CD1d and BfaGCs, (3) the structure and immunomodulatory activity of previously uncharacterized lipid species of symbiont origin and (4) the modulation of inflammatory responses by symbiont-derived CD1d ligands in vivo. The proposed studies will provide valuable knowledge of the molecular mechanisms by which symbiotic microbiota-derived molecules modulate the host immune system and help the development of potential immunotherapeutics.

肠道共生微生物来源的CD1d配体及其免疫调节机制 项目摘要 共生微生物群与哺乳动物宿主共同进化了数千年，宿主已经发展出一种 用于区分病原体和肠道微生物的复杂系统。与病原体不同， 分子引发强烈的炎症和免疫反应，共生体衍生的分子因子已被 它们被认为是“沉默的”，即使它们以非常高的密度驻留在宿主内。但最近的研究 强烈表明共生起源分子因子积极地促进宿主免疫调节， 防止过度炎症。我们以前已经确定并表征了一类独特的脂质 （α-半乳糖神经酰胺）来自人肠道共生体脆弱拟杆菌，可调节宿主免疫 生命早期的发展。我们的初步结果表明，这些分子（BfaGCs）是由 非经典的MHC I类分子CD1d在结构上保守的方式类似于记录 for prototypic原型CD1d ligands配体.值得关注的是，与CD1d激动剂如KRN 7000不同，BfaGCs的功能 作为自然杀伤T（NKT）细胞的调节因子，NKT细胞是一种受CD1d-脂质抗原限制的特异性T细胞亚型 复杂.合成的BfaGC分子可以从NKT细胞诱导不同的免疫调节信号，并且可以 作为结肠中NKT细胞增殖的调节剂发挥作用。此外，肠道的靶向脂质组学分析 symbionts已经在多种肠道共生体中鉴定出与BfaGC结构相关的脂质种类，这意味着 肠道共生体可以共同合成潜在的NKT细胞调节剂。我们建议调查 分子免疫调节机制的基础上的活动，肠道共生衍生的脂质配体。我们 目的是确定（1）由CD1d-BfaGC复合物识别的不同NKT群体及其 对BfaGCs的免疫调节反应，（2）CD1d和BfaGCs之间的特异性分子水平相互作用， BfaGCs，（3）以前未表征的脂质种类的结构和免疫调节活性， 共生体起源和（4）共生体衍生的CD1d配体在体内对炎症反应的调节。 拟议的研究将为共生的分子机制提供有价值的知识 微生物群衍生的分子调节宿主免疫系统，并帮助发展潜力 免疫治疗