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.