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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结