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Determinants of induced Treg and inflammatory Th17 cell balance in response to potentially pathogenic microbiota

诱导 Treg 和炎症 Th17 细胞平衡响应潜在致病微生物群的决定因素

基本信息

批准号：
10372223
负责人：
Dan Littman
金额：
$ 52.11万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
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：
2021-03-15 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10372223
关键词：
Adopted Affect Antibodies Antigen Presentation Antigen-Presenting Cells Autoimmune Diseases Bacteria Bone Marrow CD4 Positive T Lymphocytes Cell Communication Cell Differentiation process Cell Line Cell physiology Cells Characteristics Chimera organism Chronic Colon Complement Cre driver Crohn&apos s disease Dangerousness Data Data Set Dendritic Cells Docking Endothelial Cells Environmental Exposure Environmental Risk Factor Epithelial Cells Equilibrium Exposure to FOXP3 gene Genetic Genetic Models Genetic Predisposition to Disease Goals Health Benefit Helicobacter hepaticus Histocompatibility Antigens Class II Homeostasis ITGAX gene Immune system Impairment In Vitro Infection Inflammation Inflammatory Inflammatory Bowel Diseases Integrin alphaV Interleukin-10 Intestines Lamina Propria Lead Leukocytes Location Lymphoid Cell MHC Class II Genes Maintenance Mediating Microbe Mouse Strains Mus Mutant Strains Mice Mutate Mutation Myeloid Cells Pathogenicity Pathway interactions Phenotype Physiological Population Process Province Regulation Regulatory T-Lymphocyte Reporter Research Risk Role Specific qualifier value Study models System T cell differentiation T cell response T-Cell Activation T-Lymphocyte Therapeutic Transforming Growth Factor alpha Transforming Growth Factor beta Transgenic Organisms Tumor Immunity Ulcerative Colitis Wild Type Mouse Work cell type commensal bacteria cytokine dysbiosis embryonic stem cell experimental study gut inflammation gut microbiota immunological synapse formation intestinal barrier intestinal homeostasis intravital microscopy lymph nodes macrophage mesenteric lymph node microbial microbiota microorganism migration multiphoton microscopy new therapeutic target pathobiont pathogen programs receptor response single-cell RNA sequencing spatiotemporal transcription factor transcriptomics villin

项目摘要

Interactions of the gut microbiota with cells of the immune system govern multiple physiological functions that are manifested locally, in the regulation of intestinal barrier functions, and systemically, in autoimmune diseases and modulation of anti-tumor immunity. Although mutualistic microbial species generally provide vital health benefits to the host, some of them can conditionally cause harm under some circumstances, such as host genetic vulnerabilities or following environmental perturbation. These bacterial species, known as “pathobionts”, have been proposed to be major contributors to inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn’s disease, which are characterized by intestinal dysbiosis. A better characterization of these bacterial species and the mechanisms by which they interact with the host in healthy homeostatic conditions and during IBD-associated inflammation is critical for developing better therapeutic approaches. We study the model pathobiont Helicobacter hepaticus, which induces regulatory T cells (iTreg) in the healthy murine gut, but promotes Th17-mediated inflammation when the iTregs are compromised. H. hepaticus- specific naïve T cells are activated by antigen-presenting cells (APCs) in colon-draining mesenteric lymph nodes (mLN), and up-regulate Foxp3 and RORgt, transcription factors characteristic of intestinal iTreg. However, when IL-10 is limiting or when iTreg induction is otherwise compromised, the microbe-specific T cells express RORgt and adopt a pathogenic (p)Th17 cell program in the lamina propria. The goals of this proposal are to identify the APCs that interact with naïve H. hepaticus-specific T cells in the mLN to program either iTreg or pTh17 differentiation pathways, elucidate the molecules involved and the temporal dynamics of the APC-T cell interactions, and determine the roles of the diverse types of MHC class II-expressing cells in the intestinal lamina propria in promoting iTreg and pTh17 cell functions. In preliminary studies, we found that selective loss of either CCR7 in dendritic cells (DCs) or MHC-II in type 3 innate lymphoid cells (ILC3) resulted in abrogation of iTreg cell differentiation and in expansion, instead, of pTh17 cells in mLN and lamina propria. A similar iTreg phenotype was observed when molecules involved in TGF-b release were mutated in DCs or ILC3, suggesting that regulated local release of this iTreg-inducing cytokine requires naïve T cells to interact with both DCs and ILC3. Our first aim is to precisely characterize, through genetic and transcriptomic approaches, the cell types required for iTreg induction in the mLN, and rule out potential for misinterpretation due to expression of Cre in rare uncharacterized APCs or to indirect effects of the cell type-restricted mutations; and determine the spatiotemporal interactions of the cells, using multiphoton microscopy. The second aim is to identify the CCR7- independent APC(s) required for pTh17 cell induction in settings of compromised iTreg induction. The third aim is to leverage the H. hepaticus-specific system to investigate potential non-T cell priming functions of diverse MHC-II-expressing cell types in the intestinal lamina propria, including epithelial and endothelial cells.

肠道微生物群与免疫系统细胞的相互作用控制着多种生理功能