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: 10317582
• 负责人: De'Broski R Herbert
• 金额: $ 39.57万
• 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/10317582
• 关键词: Acute; Anti-Inflammatory Agents; Antigen-Presenting Cells; Automobile Driving; B-Lymphocytes; Biological; Cell Lineage; Cell Shape; Cells; Cellular Structures; 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 Response; Interferon Type II; Interleukin-1; Interleukin-17; Interleukins; Intestines; Lymphocyte Subset; Lymphoid; Lymphoid Cell; Maintenance; Mass Spectrum Analysis; 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; inflammatory disease of the intestine; intestinal crypt; intestinal epithelium; intestinal homeostasis; macrophage; 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.

项目概要 白细胞介素 1 (IL-1) 细胞因子超家族成员 IL-33 促进宿主免受胃肠道 (GI) 侵害 病原体通过尚不清楚的机制。矛盾的是，IL-33 的反应性在不同 淋巴细胞亚群决定了其促炎作用与抗炎作用，这通过其促进淋巴细胞扩张的能力来证明。 分别为第 2 组先天淋巴细胞 (ILC2) 或 Foxp3+ 调节性 T 细胞 (Treg)。 IL-33是否来源 由于目前的范式认为 IL-33 仅从 结构细胞受损（例如上皮细胞谱系）。然而，我们最近发表的数据表明，肠道 上皮细胞 (IEC) 衍生的 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 反应和蠕虫易感性。该提案旨在了解 负责骨髓谱系中 IL-33 表达和产生的机制并进一步研究 IL-33 细胞环境是否控制炎症与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中心假设 IL-33 的来源决定了 IL-33 在胃肠道寄生虫过程中是否发挥保护作用或致病作用 通过控制肠道 Treg 亚群扩张来控制感染。我们将在两个特定的情况下检验这个假设 目标（SA）。 SA1 中提出的实验将： a) 转录分析 IL-33+ 与 IL-33- DC 以确定是否 表达 IL-33 的 APC 构成了一个独特的子集，b) 采用显微镜和成像质谱法来 了解这些细胞所在的组织生态位，并且 c) 确定 DC 衍生的 IL-33 是否对于 通过微生物依赖性机制维持和/或诱导 Foxp3+ Treg 的不同亚群。 SA2 将产生允许在不同的 DC 亚群和组织巨噬细胞群中删除 IL-33 的小鼠，以 确定它们对肠道组织稳态和宿主针对胃肠道病原体的保护的影响。最后，我们将 确定上皮细胞与骨髓来源的 IL-33 是否控制微生物失调和病理结果 口腔弓形虫感染后。总而言之，该项目旨在扩大基本理解 研究细胞因子产生的细胞背景如何影响对重要人类胃肠道病原体的免疫力。