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（由申请人提供）：我们提出，视黄酸（RA）调节粘膜适应性免疫反应，控制定型（Th1、Treg、CD8eff）T 细胞的命运。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 谱系特异基因以及指导 Th17 细胞命运的抑制基因的稳定表达。我们的研究确定 RA-RARα 是调控网络的关键组成部分。控制 Th1 细胞命运并定义 Th1aTh17 分化的新范式，这些发现对观察到 Th1-Th17 反应失调的肠道免疫具有重要意义。最后，通过特定受体亚型的 RA 信号传导受损会限制 CD8 T 细胞的存活和分化，因此，我们认为 RA 的这些功能在宿主抵抗传染病方面发挥着重要作用。使用允许体内 RA 信号传导谱系特异性控制的遗传模型，我们将： 1. 定义 RA 在 Th1 稳定性中的作用我们发现 RA 控制 Th1 T 细胞中 T-bet 的表达水平，从而控制 Th1 谱系的维持。信号发育为双阳性、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 细胞和 T 细胞中 RAR 调节的直接靶标。最后，鉴于 RA 组织水平控制 T 细胞定向的关键事件，我们将提供关于 RA 如何编程 T 细胞谱系维持和表型的重要生物学线索。利用遗传模型，可以在所选谱系中特异性消除 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 在维持肠道中选择性沉默中的作用。 Foxp3 中的 RA 信号传导我们所追求的显着炎症综合征的出现是由于 Treg 谱系不稳定和功能障碍造成的。有人提出，自然和适应性 Treg 功能都被消除，并且将解决潜在的细胞和分子机制。 RA 在肠道 CD8 谱系定型中的作用我们已经确定了 RARa 与 RARb 在 CD8+ T 细胞生物学中的具体独特贡献，RARa 对于 T 细胞的存活至关重要，而 RARb 对于 T 细胞的存活至关重要。这些方法为全面定义 RAR 亚型在 CD8+ T 细胞稳定性、存活、扩增和记忆发育中的作用提供了新颖且令人兴奋的机会，这将是第一个全面的研究。跟踪并量化肠道中抗原特异性 CD8+ T 细胞反应。