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.

肠道共生菌群衍生的CD1D配体及其免疫调节机制 项目摘要 共生微生物群已与哺乳动物宿主共同发展了数千年，并且宿主已经发展了 用于区分病原体和共生微生物的软化系统。与病原体不同，其中许多 分子触发鲁棒性炎症和免疫反应，象征的衍生分子因子一直是 即使他们以非常高的密度居住在主机中，也被认为是“沉默”。但是，最近的研究 强烈表明共生起源的分子因子积极促进宿主免疫调节和 防止过量炎症。我们以前已经确定并表征了独特的脂质类 （α-半乳糖基酰胺）来自人类肠道符号菌属的fragilis，可以调节宿主免疫 生命早期发展。我们的初步结果表明，这些分子（BFAGC）由 以结构配置的方式类似于该记录 用于原型CD1D配体。引人注目的是，与CD1D激动剂（例如KRN7000）不同，BFAGCS功能 作为天然杀伤t（NKT）细胞的调节剂，特定的T细胞亚型受CD1D – Lipid抗原的限制 复杂的。合成BFAGC分子可以诱导NKT细胞的不同免疫调节信号，并且可以 功能是结肠中NKT细胞增殖的调节剂。此外，肠道的靶向脂肪组分析 共生体已经确定了与bfagcs在多个肠道符号中结构上相关的脂质物种，这意味着 肠道符号可以集体合成潜在的NKT细胞调节剂。我们建议对 分子免疫调节机制是肠道丝螺式脂质配体活性的基础。我们 旨在确定（1）CD1D-BFAGC综合体认识的独特的NKT种群及其 对BFAGC的免疫调节反应，（2）CD1D和 BFAGC，（3）先前未表征的脂质物种的结构和免疫调节活性 共生体的起源和（4）在体内通过共生体衍生的CD1D配体对炎症反应的调节。 拟议的研究将提供有关共生的分子机制的宝贵知识 微生物群衍生的分子调节宿主免疫系统，并有助于发展潜力 免疫治疗药。