Effect of XBP1-deficiency in DCs on CNS pathology

Dendritic cells (DCs) control the generation of self-reactive pathogenic T cells. Thus, DCs are attractive therapeutic targets for autoimmune diseases. Using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies we identified a negative feedback regulatory pathway that operates in DCs to limit immunopathology. Specifically, we found that lactate, produced by activated DCs and other immune cells, boosts NDUFA4L2 expression through a mechanism mediated by HIF-1a. NDUFA4L2 promotes mitochondrial fitness in DCs, limiting the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules involved in the control of pathogenic autoimmune T cells. Moreover, we engineered a probiotic that produces lactate and suppresses T-cell autoimmunity in the central nervous system via the activation of HIF-1a/NDUFA4L2 signaling in DCs. In summary, we identified a novel immunometabolic pathway that regulates DC function, and developed a synthetic probiotic for its therapeutic activation via the gut-brain axis. Overall design: Experimental autoimmune encephalomyelitis was induced in Itgax Cre Xbp1 flox and WT mice and dendritic cells were sorted from Central Nervous System and spleen.