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Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells

Sanmarco, LM;Rone, JM;Polonio, CM;Fernandez Lahore, G;Giovannoni, F;Ferrara, K;Gutierrez-Vazquez, C;Li, N;Sokolovska, A;Plasencia, A;Faust Akl, C;Nanda, P;Heck, ES;Li, Z;Lee, HG;Chao, CC;Rejano-Gordillo, CM;Fonseca-Castro, PH;Illouz, T;Linnerbauer, M;Kenison, JE;Barilla, RM;Farrenkopf, D;Stevens, NA;Piester, G;Chung, EN;Dailey, L;Kuchroo, VK;Hava, D;Wheeler, MA;Clish, C;Nowarski, R;Balsa, E;Lora, JM;Quintana, FJ;

Dendritic cells (DCs) have a role in the development and activation of self-reactive pathogenic T cells1,2. Genetic variants that are associated with the function of DCs have been linked to autoimmune disorders3,4, and DCs are therefore attractive therapeutic targets for such diseases. However, developing DC-targeted therapies for autoimmunity requires identification of the mechanisms that regulate DC function. Here, using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies, we identify a regulatory loop of negative feedback that operates in DCs to limit immunopathology. Specifically, we find that lactate, produced by activated DCs and other immune cells, boosts the expression of NDUFA4L2 through a mechanism mediated by hypoxia-inducible factor 1? (HIF-1?). NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs that are involved in the control of pathogenic autoimmune T cells. We also engineer a probiotic that produces lactate and suppresses T cell autoimmunity through the activation of HIF-1?-NDUFA4L2 signalling in DCs. In summary, we identify an immunometabolic pathway that regulates DC function, and develop a synthetic probiotic for its therapeutic activation.