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Retinoic acid in gut immune homestatis and infection

视黄酸在肠道免疫稳态和感染中的作用

基本信息

批准号：
8913568
负责人：
RANDOLPH J. NOELLE
金额：
$ 60.98万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-15 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8913568
关键词：
Ablation Address Antigens Architecture Area Autoimmunity Back Bacteria Binding Biological CD8B1 gene Cell Differentiation process Cell Lineage Cell Survival Cells Cellular biology Communicable Diseases Data Development Disease Disease model Dominant-Negative Mutation Educational process of instructing Employee Strikes Enhancers Equilibrium Eragrostis Event Functional disorder Gene Expression Profile Genes Genetic Models Graft Rejection Hematopoietic Host resistance IL17 gene Immune Immune response Immunity Immunization Impairment In Vitro Infection Infiltration Inflammatory Inflammatory Bowel Diseases Leukocytes Listeria monocytogenes Literature Maintenance Memory Molecular Monitor Mucosal Immunity Mus Oral Pathway interactions Phenotype Predisposition Preschool Child Protein Isoforms Publishing Regulation Regulatory T-Lymphocyte Reporting Repression Resistance Role STAT4 gene Signal Transduction Specific qualifier value Supporting Cell Syndrome Systemic infection T cell response T-Lymphocyte Th1 Cells Time Tissues Tretinoin Vitamin A Work adaptive immunity base comparative genetic approach improved in vivo mucosal site novel oral infection overexpression pathogen prevent programs public health relevance receptor response

项目摘要

DESCRIPTION (provided by applicant): We propose that retinoic acid (RA) regulates mucosal adaptive immune response controlling the fate of committed (Th1, Treg, CD8eff) T cells. In the absence of RA signaling, we show that RA, through its receptor RARα, sustains stable expression of Th1 lineage specifying genes as well as repressing genes that instruct Th17 cell fate. Our studies identify RA-RARα as a key component of the regulatory network governing Th1 cell fate and define a new paradigm of Th1aTh17 differentiation. These findings have important implications for gut immunity in which dysregulated Th1-Th17 responses are observed. We further show that ablation of RA signaling in the Foxp3 lineage ablates in vivo Treg function. Finally, impairment of RA signaling of through specific receptor isoforms limits CD8 T cell survival and differentiation. As such, we propose that these functions of RA are prominent in its role in host resistance to infectious disease. Using genetic models that allow lineage specific control of RA signaling in vivo we will: 1. Define the role of RA in Th1 stability and repression of Th1aTh17 differentiation in the gut in vivo. We show that RA controls the level of T-bet expression in Th1 T cells and as such controls Th1 lineage maintenance. Furthermore, we show that T cells which are deprived of an RA signal develop into double positive, IL17+, IFNgLow T cells and Th17 cells. RARa CHIPseq studies and transcriptome analysis have identified for the first time, direct targets for RAR regulation in T cells and provie important biological leads as to how RA programs T cell lineage maintenance and phenotype. Finally, given the fact that RA tissue levels control critical events in T cell commitment, we will exploit the use of genetic models where RA synthesis can be specifically ablated in the lineage of choice to determine the RA-synthesizing cells that support T cell fate in vivo. 2. Define the role of RA in sustaining Treg function in the gut. Selective silencing of RA signaling in the Foxp3 lineage, results in the emergence of a striking inflammatory syndrome that we hypothesize is due to Treg lineage instability and dysfunction. It is proposed that both natural and adaptive Treg function is ablated and the underlying cellular and molecular mechanisms will be addressed. 3. Understanding the role of RA in CD8 lineage commitment in the gut. We have defined specific distinctive contributions of RARa vs RARb in CD8 T cell biology. In CD8+ T cells, RARa is critical for T cell survival and RARb is critical for antigen-specific T cell expansion. These approaches provide the novel and exciting opportunity to fully define the role of RAR isoforms in CD8+ T cell stability, survival, expansion and development of memory. A comprehensive set of studies is presented which will represent the first to track and quantify the antigen-specific CD8+ T cell responses in the gut.