Myeloid derived IL-33 controls Treg responses during parasite infection

骨髓源性 IL-33 控制寄生虫感染期间的 Treg 反应

• 批准号: 10463791
• 负责人: De'Broski R Herbert
• 金额: $ 39.54万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-06 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10463791
• 关键词: Acute; Anti-Inflammatory Agents; Antigen-Presenting Cells; Automobile Driving; B-Lymphocytes; Biological; Cell Lineage; Cell Shape; Cells; Chronic; Confocal Microscopy; Cre driver; Data; Defect; Dendritic Cells; Development; Disease; Epithelial; Epithelial Cells; Equilibrium; FOXP3 gene; GATA3 gene; Gastrointestinal tract structure; Gene Expression Profile; Genetic Transcription; Helminths; Homeostasis; Human; Ileitis; Immune; Immunity; Immunosuppression; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interferon Type II; Interleukin-1; Interleukin-17; Interleukins; Intestines; Lymphocyte Subset; Lymphoid; Lymphoid Cell; Maintenance; Mus; Myelogenous; Natural Immunity; Natural regeneration; Oral; Organ; Orphan; Outcome; PTPNS1 gene; Parasites; Parasitic infection; Pathogenicity; Pathologic; Population; Predisposition; Production; Protozoan Infections; Publishing; Regulation; Regulatory T-Lymphocyte; Reporting; Resistance; Retinoic Acid Receptor; Role; Source; T cell response; Testing; Tissues; Toxoplasma gondii; Toxoplasmosis; Vaccine Therapy; XCR1 gene; adaptive immunity; cytokine; dysbiosis; experimental study; gastrointestinal; gut microbiota; helminth infection; immunopathology; intestinal crypt; intestinal epithelium; intestinal homeostasis; macrophage; mass spectrometric imaging; member; microbial; microscopic imaging; pathogen; receptor; residence; response; tissue repair; transcription factor; transcriptome sequencing; vaccination strategy

Project Summary The interleukin 1 (IL-1) cytokine superfamily member IL-33 drives host protection against gastrointestinal (GI) pathogens through mechanisms that remain unclear. Paradoxically, IL-33 responsiveness in different lymphocyte subsets dictates its pro- vs. anti-inflammatory roles evinced by its ability to promote expansion of group 2 innate lymphoid cells (ILC2) or Foxp3+ regulatory T cells (Tregs), respectively. Whether source of IL-33 influences its biological role has been largely ignored due the current paradigm that IL-33 is only released from damaged structural cells (e.g. epithelial cell lineages). However, our recently published data show that intestinal epithelial cell (IEC)-derived IL-33 drives ILC2 responses and GI helminth immunity, whereas dendritic cell (DC)- derived IL-33 drives ST2+Foxp3+ Treg responses and helminth susceptibility. This proposal seeks to understand the mechanisms responsible for IL-33 expression and production in the myeloid lineage and further investigates whether IL-33 cellular context controls the balance between inflammation vs. immunosuppression during protozoan infections as it does in helminth infections. Our project tests the central hypothesis that cellular source of IL-33 determines whether IL-33 serves a protective or pathogenic role during GI parasite infection through controlling intestinal Treg subset expansion. We will test this hypothesis in two specific aims (SA). Experiments proposed in SA1 will: a) transcriptionally profile IL-33+ vs. IL-33- DC to determine whether IL-33 expressing APC constitute a distinct subset, b) employ microscopy and imaging mass spectrometry to understand the tissue niches where these cells reside, and c) determine whether DC-derived IL-33 is critical for the maintenance and/or induction of distinct subsets of Foxp3+ Treg through microbial-dependent mechanisms. SA2 will generate mice that allow IL-33 deletion in distinct DC-subsets and tissue macrophage populations to determine their impact on intestinal tissue homeostasis and host protection against GI pathogens. Lastly, we will determine whether epithelial vs. myeloid derived-IL-33 controls microbial dysbiosis and the pathological outcome following oral Toxoplasma gondii infection. Taken together, this project seeks to expand the basic understanding of how the cellular context of cytokine production impacts immunity against important human GI pathogens.

项目摘要 白介素1(IL-1)细胞因子超家族成员IL-33驱动宿主对胃肠道(GI)的保护 病原体通过尚不清楚的机制传播。矛盾的是，IL-33的反应性在不同的 淋巴细胞亚群决定了它的促炎和抗炎作用，表现为它能够促进 第2组为固有淋巴样细胞(ILC2)或Foxp3+调节性T细胞(Tregs)。IL-33的来源 对其生物学作用的影响在很大程度上被忽视了，因为目前的范式只释放IL-33 结构细胞受损(如上皮细胞谱系)。然而，我们最近公布的数据显示，肠道 上皮细胞(IEC)来源的IL-33驱动ILC2反应和胃肠道蠕虫免疫，而树突状细胞(DC)- 衍生的IL-33驱动ST2+Foxp3+Treg反应和蠕虫敏感性。这项提议试图理解 IL-33在髓系细胞中表达和产生的机制及其进一步研究 IL-33细胞环境是否控制炎症和免疫抑制之间的平衡 原生动物感染，就像蠕虫感染一样。我们的项目测试了细胞的核心假设 IL-33的来源决定了IL-33在胃肠道寄生虫中起保护作用还是致病作用 通过控制肠道Treg亚群的扩张而感染。我们将通过两个具体的例子来检验这一假设 AIMS(SA)。在SA1中提出的实验将：a)转录分析IL-33+与IL-33-DC，以确定 表达APC的IL-33构成一个不同的亚群，b)使用显微镜和成像质谱学来 了解这些细胞所在的组织生态位，以及c)确定DC来源的IL-33是否对 通过微生物依赖机制维持和/或诱导不同的Foxp3+Treg亚群。 SA2将产生允许IL-33在不同DC亚群和组织巨噬细胞群中缺失的小鼠 确定它们对肠道组织动态平衡和宿主对胃肠道病原体的保护作用。最后，我们将 确定上皮源性IL-33与髓源性IL-33是否可控制微生物失调及其病理结果 在口服弓形虫感染后。综上所述，这个项目试图扩大对 细胞因子产生的细胞环境如何影响对重要人类胃肠道病原体的免疫力。