Background and Objectives Upon the encounter of pathogens, dendritic cells (DCs) undergo a process of maturation, which allows them to initiate and orchestrate T-cell-driven immune responses. To avoid random T-cell activation and autoimmunity, respectively, DC maturation has to be tightly controlled. Here we aimed to elucidate the role of 12/15-lipoxygenase (12/15-LO)-mediated enzymatic lipid oxidation during DC-activation/maturation and the fine-tuning of the consecutive T-cell response.
Materials and Methods To delineate the role of 12/15-LO in DCs, we analysed the phenotype of 12/15-/- bone marrow-derived DCs and performed the model of experimental autoimmune enzephalomyelitis (EAE) in wild type and 12/15-LO-/- mice.
Results Differentiated bone marrow-derived DCs expressed 12/15-LO and were enriched in 12/15-LO-specific lipid oxidation products. Deletion of this enzyme resulted in enhanced DC maturation and a shift in their cytokine expression profile, which favoured the differentiation of Th17 T-cells. In contrast, both the activation of DCs and the development of Th17 T-cells were attenuated by exposure to 12/15-LO-derived oxidised phospholipids. The analysis of the lymphatic tissues of 12/15-LO-deficient mice confirmed an enhanced maturation of CD11c+CD11b+CD8- DCs as well as an increased differentiation of Th17 cells that was paralleled by an exacerbation of Th17-driven autoimmune disease.
Conclusions Our data identify 12/15-LO as novel factor modulating the function of DCs and indicate a central, and so far unrecognised, role for enzymatic lipid oxidation during the shaping of the adaptive immune response.