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

• 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
• 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

 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(申请人提供)：我们建议维甲酸(RA)调节粘膜获得性免疫反应，控制承诺(Th1，Treg，CD8effT细胞)的命运。在没有RA信号的情况下，我们发现RA通过其受体RARα维持Th1谱系特定基因的稳定表达，以及抑制指示Th17细胞命运的基因。我们的研究确认RA-RARα是控制Th1细胞命运的调控网络的关键组成部分，并定义了Th1aTh17分化的新范式。这些发现对肠道免疫有重要意义，在肠道免疫中观察到Th1-Th17反应失调。我们进一步证明，在体内，Foxp3谱系中RA信号的消融会消融Treg功能。最后，通过特定受体亚型的RA信号受损限制了CD8T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的作用是突出的。使用允许在体内对RA信号进行谱系特异性控制的遗传模型，我们将：1.确定RA在Th1稳定性中的作用 体内抑制Th1a、、Th17的分化。我们发现RA控制Th1T细胞中T-bet的表达水平，并因此控制Th1谱系的维持。此外，我们还发现，失去RA信号的T细胞发育成双阳性、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细胞中RAR调节的直接靶点，并为RA如何规划T细胞谱系维持和表型提供了重要的生物学线索。最后，考虑到RA组织水平控制T细胞承诺的关键事件的事实，我们将 利用遗传模型，其中RA合成可以在选择的谱系中被特异性地消融，以确定支持体内T细胞命运的RA合成细胞。2.明确RA在维持肠道Treg功能中的作用。Foxp3中RA信号的选择性沉默 家系，导致一种显著的炎症综合征的出现，我们假设是由于Treg血统的不稳定和功能障碍。有人提出，自然和适应性Treg功能都被消融，其潜在的细胞和分子机制将被解决。3.了解RA在肠道CD8谱系承诺中的作用。我们已经确定了RARa和RARb在CD8T细胞生物学中的独特贡献。在CD8+T细胞中，RARa对T细胞的存活至关重要，而RARb对抗原特异性T细胞的增殖至关重要。这些方法提供了新的和令人兴奋的机会，以充分确定RAR亚型在CD8+T细胞稳定、存活、扩展和记忆发育中的作用。提出了一套全面的研究，这将是第一次跟踪和量化肠道中抗原特异的CD8+T细胞反应。