Immunomodulatory function of inflammasomes in human primary dendritic cells

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Dendritic cells (DCs) play a pivotal role in orchestrating immune responses. Equipped with various receptors in the membrane, DCs sense the tissue microenvironment for danger signals and pathogens. Inflammasomes play a pivotal role in the immune response against certain pathogens, but also in the pathogenesis of inflammatory disorders and cancer. The formation of this multiprotein signaling complex requires a TLR-mediated initial priming step and a second activation step leading to the secretion of the bioactive cytokines. Usually, the activation of the inflammasome induces pyroptosis, an inflammatory cell death mediated by the activation of caspase-1. Previously, we could show that human cDC2 can enter a state of hyperactivation, which is characterized by inflammasome activation in the absence of pyroptosis. For human cDC2, two subpopulations, namely DC2 and DC3, with so far unclear functional specialization have been recently described. Our preliminary data suggest that DC2 and DC3 differ in their response to hyperactivating inflammasome ligands. Moreover, we have hints that in human breast cancer biopsies the ratio of DC2 to DC3 is associated with certain breast cancer subtypes, indicating a subset specific function in tumor control. Further, the inflammasome ligand oxPAPC, a mixture of oxidized phospholipids, induced a rather immunosuppressive phenotype in human cDC2. Such oxidized phospholipids have been identified in tumors underlining a potential role in the immunosuppression of cDC2 subsets. We here hypothesize that DC2 and DC3 exert different roles in the polarization of immune responses in dependency on the inflammasome stimulus. Understanding the inflammasome-mediated immunomodulation is important for advancing therapies for tumors and autoimmune diseases. In the here proposed project, we will focus on the functional characterization of the two human primary cDC2 subpopulations. We further will study the regulation of hyperactivation versus tolerance/immunosuppression in the human DC subpopulations.