Role of AHR in Dendritic Cells in the Control of CNS Autoimmunity

树突状细胞 AHR 在控制中枢神经系统自身免疫中的作用

• 批准号: 10375015
• 负责人: Francisco J. Quintana
• 金额: $ 37.22万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375015
• 关键词: Adenosine; Agonist; Anti-Inflammatory Agents; Aryl Hydrocarbon Receptor; Autoimmune; Autoimmune Diseases; Autoimmunity; CNS autoimmunity; Cell physiology; Cells; Clinical; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; Engineered Probiotics; Epigenetic Process; Eragrostis; Escherichia coli; Experimental Autoimmune Encephalomyelitis; Experimental Models; Gene Expression; Generations; Genetic Transcription; Genomics; Goals; Grant; Human; Immune; Immune Targeting; Immune response; Immune system; Inflammatory; Knockout Mice; Lead; Ligands; Mediating; Multiple Sclerosis; Mus; Myelin; NF-kappa B; Names; Neuraxis; Neurologic; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Phenotype; Play; Pre-Clinical Model; Publishing; Receptor Activation; Regulation; Regulatory T-Lymphocyte; Role; Sampling; Signal Pathway; Signal Transduction; Source; System; T cell differentiation; T cell response; T-Lymphocyte; Therapeutic; Therapeutic Effect; Transcriptional Regulation; Work; base; conditional knockout; cytokine; disorder control; extracellular; gut-brain axis; indoleacetic acid; interest; macrophage; microbial; microbiome; multiple sclerosis patient; multiple sclerosis treatment; novel; novel therapeutic intervention; novel therapeutics; programs; response; single-cell RNA sequencing; therapeutic target; tool; transcription factor

PROJECT SUMMARY Effector and regulatory T cells targeting the central nervous system (CNS) play a pivotal role in the pathogenesis of multiple sclerosis (MS) and its model experimental autoimmune encephalomyelitis (EAE). Dendritic cells (DCs) control CNS-specific T cells, but the pathways regulating DC function are poorly characterized. Published studies suggest a role for the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) in the control of DCs. During the previous grant cycle we have made the following findings: 1) Deletion of AHR expressed in classical DCs (AHRcDC) worsens EAE and exacerbates autoimmune T-cell responses, 2) Single-cell RNA-seq analyses of mouse and human classical DCs (cDCs) detected the coordinated expression of AHR with the transcription factor KLF4 and the ectoenzyme CD39, 3) Indeed, AHRcDC drives the expression of KLF4 in cDCs (KLF4cDC), a transcription factor known to limit NF-kB activation and drive anti-inflammatory gene expression in macrophages, 4) KLF4cDC deletion worsens EAE and exacerbates pathogenic T-cell responses, 5) AHRcDC also drives the expression of CD39 in cDCs (CD39cDC), which degrades pro-inflammatory extracellular ATP (eATP) and participates in the synthesis of anti-inflammatory adenosine, 5) CD39cDC deletion worsens EAE and exacerbates pathogenic T-cell responses, 6) AHR activation induces mouse and human tolerogenic cDCs, and 7) A novel probiotic engineered to produce the AHR agonist IAA (named EcNIAA) suppresses EAE in an AHRcDC-dependent manner. Based on these findings we hypothesize that AHRcDC-driven KLF4 and CD39 expression in cDCs limits CNS autoimmunity. Our specific aims are: Specific Aim 1: DETERMINE THE ROLE OF KLF4 IN THE CONTROL OF cDCS BY AHRcDC. We propose to: 1) Define KLF4-dependent and KLF4-independent transcriptional programs controlled by AHRcDC in single cell and bulk genomic studies, and 2) Establish the role of KLF4 in the control of NF-kB by AHR in cDCs. Specific Aim 2: ESTABLISH THE ROLE OF CD39 IN THE CONTROL OF T CELLS BY AHRcDC. We propose to: 1) Define the effects of AHRcDC-induced CD39cDC expression on myelin-specific T cells, 2) Determine whether the AHRcDC-CD39cDC axis promotes regulatory T cell differentiation, and 3) Establish the roles of AHRcDC, KLF4cDC and CD39cDC in the control of T cells by DCs in healthy controls and MS patients. Specific Aim 3: DEFINE THE ROLE OF AHRcDC IN EAE SUPPRESSION BY EcNIAA. This aim evaluates the therapeutic potential of activating AHRcDC with EcNIAA, a novel probiotic engineered to produce the AHR agonist IAA. We propose to: 1) Evaluate the therapeutic effects of EcNIAA in EAE, 2) Define the roles of AHRcDC and KLF4cDC on the transcriptional modulation of DCs by EcNIAA, 3) Establish the contribution of AHRcDC and CD39cDC to the control of effector and regulatory T cells by EcNIAA. IN SUMMARY, in this competitive renewal we use unique tools and clinical samples to study a novel aspect of AHRcDC as a regulator of T-cell autoimmunity, and its potential as a therapeutic target in autoimmune diseases.

项目摘要 靶向中枢神经系统（CNS）的效应和调节性T细胞在中枢神经系统（CNS）中起关键作用。 多发性硬化（MS）及其实验性自身免疫性脑脊髓炎（EAE）模型的发病机制。 树突状细胞（DC）控制CNS特异性T细胞，但调节DC功能的途径很少 表征了已发表的研究表明，配体激活的转录因子芳烃 受体（AHR）在DC的控制。在上一个赠款周期，我们有以下发现：1） 经典DCs中表达的AHR缺失（AHRcDC）可导致EAE并加重自身免疫性T细胞 2）小鼠和人经典DC（cDC）的单细胞RNA-seq分析检测了小鼠和人经典DC（cDC）的单细胞RNA-seq分析。 AHR与转录因子KLF 4和胞外酶CD 39的协调表达，3）事实上，AHRcDC 驱动KLF 4在cDC（KLF 4cDC）中的表达，KLF 4cDC是一种已知限制NF-kB活化并驱动KLF 4表达的转录因子。 巨噬细胞中的抗炎基因表达，4）KLF 4cDC缺失导致EAE并加重 5）AHRcDC还驱动cDC中CD 39（CD 39 cDC）的表达，其降解 促炎性细胞外ATP（eATP）并参与抗炎腺苷的合成，5） CD 39 cDC缺失导致EAE并加剧致病性T细胞应答，6）AHR激活诱导小鼠 和人致耐受性cDC，和7）经工程化以产生AHR激动剂IAA的新型益生菌（命名为 EcNIAA）以AHRcDC依赖性方式抑制EAE。基于这些发现，我们假设， cDC中AHRcDC驱动的KLF 4和CD 39表达限制CNS自身免疫。我们的具体目标是： 具体目标1：确定KLF 4在AHRcDC控制cDCS中的作用。 我们的主要工作是：1）确定AHRcDC调控的KLF 4依赖性和KLF 4非依赖性转录程序 在单细胞和大量基因组研究中，以及2）确定KLF 4在cDC中通过AHR控制NF-κ B中的作用。 具体目标2：确定CD 39在AHRcDC控制T细胞中的作用。 我们提出：1）确定AHRcDC诱导的CD 39 cDC表达对髓鞘特异性T细胞的影响，2） 确定AHRcDC-CD 39 cDC轴是否促进调节性T细胞分化，以及3）确定AHRcDC-CD 39 cDC轴在调节性T细胞分化中的作用。 AHRcDC、KLF 4cDC和CD 39 cDC在健康对照和MS患者中通过DC控制T细胞中的表达。 具体目标3：确定AHRcDC在EAE抑制中的作用。 该目的评估了用EcNIAA激活AHRcDC的治疗潜力，EcNIAA是一种新的益生菌， 产生AHR激动剂IAA。我们建议：1）评价EcNIAA治疗EAE的疗效，2）确定 AHRcDC和KLF 4cDC在EcNIAA对DCs转录调节中的作用，3）确定AHRcDC和KLF 4cDC在EcNIAA对DCs转录调节中的作用。 AHRcDC和CD 39 cDC对EcNIAA调控效应性和调节性T细胞的作用。 总之，在这次竞争性更新中，我们使用独特的工具和临床样本来研究 AHRcDC作为T细胞自身免疫的调节剂，及其作为自身免疫性疾病治疗靶点的潜力。