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：
9205215
负责人：
RANDOLPH J. NOELLE
金额：
$ 59.46万
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/9205215
关键词：
Ablation Address Antigens Architecture Area Autoimmunity Back Bacteria Binding Biological CD8-Positive T-Lymphocytes CD8B1 gene Cell Differentiation process Cell Lineage Cell Survival Cells Cellular biology Communicable Diseases Data Development Disease Disease model Dominant-Negative Mutation Employee Strikes Enhancers Equilibrium Eragrostis Event FOXP3 gene Functional disorder 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 Pathogenicity 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-Lymphocyte Th1 Cells Time Tissues Tretinoin Vitamin A Work adaptive immune response comparative genetic approach improved in vivo mucosal site novel novel therapeutics oral infection overexpression pathogen prevent programs public health relevance receptor response retinoic acid receptor alpha transcriptome

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.

描述（由适用提供）：我们提出视黄酸（RA）调节粘膜适应性免疫响应，以控制犯罪的命运（TH1，Treg，CD8eff）T细胞。在没有RA信号传导的情况下，我们表明RA通过其受体RARα维持Th1谱系指定基因的稳定表达以及抑制指导Th17细胞命运的基因。我们的研究将RA-RARα确定为管理Th1细胞命运的监管网络的关键组成部分，并定义了TH1A的新范式。17TH17分化。这些发现对肠道免疫学具有重要意义，其中观察到失调的Th1-Th17反应。我们进一步表明，Foxp3谱系中RA信号的消融在体内Treg函数中消融。最后，通过特定的接收器同工型对RA信号的损害限制了CD8 T细胞的存活和分化。因此，我们建议RA的这些功能在宿主对传染病的抵抗中的作用很重要。使用允许体内RA信号传导特定谱系控制的遗传模型，我们将：1。定义RA在Th1稳定性中的作用 Th1a的表达th17在体内肠道中的分化。我们表明，RA控制Th1 T细胞中T-BET表达的水平，并控制Th1谱系维持。此外，我们表明，被剥夺RA信号发展为双阳性的T细胞IL17+，IFNGLOW T细胞和Th17细胞。 RARA CHIPSEQ研究和转录组分析首次确定了T细胞中RAR调节的直接靶标，并提供了有关RA计划如何编程T细胞谱系维持和表型的重要生物学铅。最后，鉴于RA组织水平控制T细胞承诺中的关键事件的事实，我们将利用遗传模型的使用，其中可以在首选谱系中特异性消融RA合成以确定支持体内T细胞命运的RA合成细胞。 2。定义RA在肠道中持续Treg功能中的作用。 FOXP3中RA信号的选择性沉默血统，导致我们假设的引人注目的炎症综合征的出现是由于Treg谱系不稳定性和功能障碍。有人提出，自然和适应性的Treg功能均已消融，并将解决潜在的细胞和分子机制。 3。了解RA在CD8谱系承诺中的作用。我们已经定义了RARA与RARB在CD8 T细胞生物学中的特定独特贡献。在CD8+ T细胞中，RARA对于T细胞存活至关重要，RARB对于抗原特异性T细胞膨胀至关重要。这些方法为充分定义RAR同工型在CD8+ T细胞稳定性，生存，扩展和记忆发展中的作用提供了新颖而令人兴奋的机会。提出了一组全面的研究，该研究将代表第一个跟踪和量化肠道中抗原特异性CD8+ T细胞反应的研究。