Engineered probiotics limit T-cell driven CNS autoimmunity by activating AHR-KLF4-FADS3 signaling in intestinal dendritic cells

Dendritic cells (DCs) control the induction of effector immune responses and tolerance. The development and function of DCs is regulated by transcriptional, epigenetic and metabolic programs, but the mechanisms controlling DC metabolism and its impact on autoimmune diseases remain poorly understood. Here, using single-cell and bulk RNA-sequencing, in vivo DC-specific gene perturbations, multiple sclerosis (MS) clinical samples and preclinical models, we identified an aryl hydrocarbon receptor (AHR) - Krüppel-like factor 4 (KLF4) - fatty acid desaturase enzyme 3 (FADS3) axis which drives the production of docosahexaenoic acid (DHA) in DCs and limits effector T-cell responses and the development of experimental autoimmune encephalomyelitis (EAE). Furthermore, we used synthetic biology approaches to engineer a probiotic (EcNIAA) that produces the AHR agonist indole-3-acetic acid (IAA) as a tool to limit pathogenic inflammatory responses. EcNIAA administration activates AHR-KLF4-FADS3 signaling in intestinal DCs, increasing DHA production and suppressing encephalitogenic T cells that originate in the gut and migrate to the central nervous system to promote autoimmune pathology. Briefly, we identified a novel immunometabolic axis that operates in DCs to limit effector T-cell responses, and can be targeted with engineered probiotics to treat autoimmunity.树突状细胞（dendritic cells, DCs）是调控效应免疫应答诱导与免疫耐受的核心细胞群体。DC的发育及功能受转录、表观遗传与代谢程序的精准调控，但控制DC代谢及其与自身免疫疾病关联的分子机制仍未被充分阐明。本研究借助单细胞与批量RNA测序技术、体内DC特异性基因扰动实验、多发性硬化（multiple sclerosis, MS）临床样本及临床前模型，鉴定出一条芳香烃受体（aryl hydrocarbon receptor, AHR）-Krüppel样因子4（Krüppel-like factor 4, KLF4）-脂肪酸去饱和酶3（fatty acid desaturase enzyme 3, FADS3）信号轴：该信号轴可介导DC内二十二碳六烯酸（docosahexaenoic acid, DHA）的合成，进而抑制效应T细胞应答与实验性自身免疫性脑脊髓炎（experimental autoimmune encephalomyelitis, EAE）的发生发展。此外，本研究通过合成生物学手段构建了一株可分泌芳香烃受体激动剂吲哚-3-乙酸（indole-3-acetic acid, IAA）的工程益生菌（EcNIAA），以此作为干预致病性炎症应答的工具。饲喂EcNIAA可激活肠道DC内的AHR-KLF4-FADS3信号通路，促进DHA合成，并抑制源自肠道、迁移至中枢神经系统以诱发自身免疫病理的致脑炎T细胞。简言之，本研究鉴定出一条全新的DC固有免疫代谢轴，该轴可限制效应T细胞应答，且可通过工程化益生菌进行靶向干预，为自身免疫疾病的治疗提供了新的潜在策略。