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The Role of Route of Entry by Bacterial Antigens on Colonic T Cell Responses

细菌抗原进入途径对结肠 T 细胞反应的作用

基本信息

批准号：
9912712
负责人：
CHYI S HSIEH
金额：
$ 55.24万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-23 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912712
关键词：
Antibiotics Antigen Presentation Antigens Automobile Driving B-Lymphocytes Bacteria Bacterial Antigens Biological Assay Cells Chronic Coculture Techniques Colon Data Dendritic Cells Development Disease Environment FOXP3 gene Flow Cytometry Goblet Cells Health Promotion Helicobacter Homeostasis Image Immune Immune response Immune system Immunity In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Intestines Investigation Knowledge Literature Location Manuscripts Mediating Metagenomics Mucosal Immune System Mucous Membrane Mus Outcome Pathogenesis Pathology Peripheral Phenotype Play Population Process Regulatory T-Lymphocyte Role Route T cell response T-Cell Development T-Lymphocyte T-cell receptor repertoire Time Work antigen-specific T cells base commensal bacteria dysbiosis effector T cell genetic approach gut bacteria gut microbiota imaging approach in vivo inflammatory disease of the intestine microbial pathobiont pathogen pathogenic bacteria prevent response transcriptome sequencing

项目摘要

Project Summary Effector T cell responses to pathogenic bacteria are crucial for protection from pathogens, but when directed toward non-pathogens, may underlie inappropriate responses driving disorders such as inflammatory bowel disease (IBD). Conversely, Foxp3+ regulatory T cell (Treg) responses to commensals enforce tolerance to prevent immune-mediated pathology such as IBD. The relative priority and context of gut bacterial interaction with the immune system remain significant gaps in our understanding. We observed that dysbiosis induces the formation of colonic goblet cell associated antigen passages (GAPs), providing an alternative route by which the immune system encounters gut resident bacteria. Further, we observed that gut resident bacteria taxa generally considered as tolerance-promoting can induce effector responses when encountered via colonic GAPs. Alternatively, we have found that antigen-specific peripheral (pTregs) largely recognize mucosal associated (MA) murine Helicobacter spp in vitro and in vivo, and that encounter of Helicobacter spp occurs continuously and is independent of GAPs. These data indicate that bacteria believed to be pathobionts can be potent inducers of pTregs during homeostasis, and in contrast, taxa believed to be tolerance inducing, Clostridia, are largely not encountered by the immune system in the steady state, but are encountered via colonic GAPs resulting in effector T cell responses. We hypothesize that the location and route of encounter of gut bacteria are important determinants of the outcome of immune responses and that the MA bacteria can play an important role in controlling the interactions and responses to gut resident bacteria encountered via colonic GAPs. In this proposal we will evaluate this hypothesis by: 1) defining the commensal antigens delivered via mucosal association (MA) and GAPs 2) defining the dendritic cell (DC) subsets involved in acquisition and presentation of mucosal associated and GAP delivered commensal antigens and 3) defining the effects of Helicobacter on the mucosal immune system and responses to GAP delivered antigens. Studies outlined in this proposal will fill the gaps in our understanding by identifying how specific bacterial taxa are encountered by the immune system and the subsequent immune responses. This knowledge can be leveraged to guide manipulations of the gut microbiota and the immune system to ‘reset’ chronic inflammatory responses and return to homeostasis.

项目总结