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: 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
• 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

 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。在缺乏 RA 信号传导的情况下，我们发现 RA 通过其受体 RARα 维持 Th1 谱系特异基因的稳定表达，并抑制指导 Th17 细胞命运的基因。我们的研究确定 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。这些发现对观察到 Th1-Th17 反应失调的肠道免疫具有重要意义。我们进一步表明 Foxp3 谱系中 RA 信号传导的消除会消除体内 Treg 功能。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 以及体内肠道中 Th1aTh17 分化的抑制。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。此外，我们表明，剥夺 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 调节的直接靶标，并为 RA 如何编程 T 细胞谱系维持和表型提供了重要的生物学线索。最后，鉴于 RA 组织水平控制 T 细胞定向中的关键事件，我们将 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 Treg 功能中的作用。 Foxp3 中 RA 信号的选择性沉默 谱系，导致出现显着的炎症综合征，我们假设这是由于 Treg 谱系不稳定和功能障碍所致。有人提出，天然和适应性 Treg 功能均被消除，潜在的细胞和分子机制将得到解决。 3. 了解 RA 在肠道 CD8 谱系定型中的作用。我们已经定义了 RARa 与 RARb 在 CD8 T 细胞生物学中的具体独特贡献。在 CD8+ T 细胞中，RARa 对于 T 细胞存活至关重要，而 RARb 对于抗原特异性 T 细胞扩增至关重要。这些方法为充分定义 RAR 同工型在 CD8+ T 细胞稳定性、存活、扩展和记忆发展中的作用提供了新颖且令人兴奋的机会。提出了一系列全面的研究，这将是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。