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Select hyperactivating NLRP3 ligands enhance the TH1- and TH17-inducing potential of human type 2 conventional dendritic cells

Type 2 conventional dendritic cells mediate superior immune responses to specific inflammasome ligands. Dendritic cells in overdrive Upon detection of danger signals, such as molecules associated with infectious pathogens, dying cells, or tumor cells, antigen-presenting cells called dendritic cells initiate adaptive immune responses. This response is enhanced through inflammasome signaling that induces cytokine secretion but usually leads to death of the activated cells. Hatscher et al. analyzed human primary DCs from the blood, spleen, and thymus and found that type 2 conventional dendritic cells (cDC2) uniquely did not die after inflammasome-induced cytokine secretion. Instead, these cells entered a “hyperactive” state that enhanced the stimulation of certain T helper cell subsets. The findings suggest that cDC2 could be critical to the efficacy of vaccines and immunotherapies as well as for therapeutically controlling inflammation. The detection of microorganisms and danger signals by pattern recognition receptors on dendritic cells (DCs) and the consequent formation of inflammasomes are pivotal for initiating protective immune responses. Although the activation of inflammasomes leading to secretion of the cytokine IL-1β is typically accompanied by pyroptosis (an inflammatory form of lytic programmed cell death), some cells can survive and exist in a state of hyperactivation. Here, we found that the conventional type 2 DC (cDC2) subset is the major human DC subset that is transcriptionally and functionally poised for inflammasome formation and response without pyroptosis. When cDC2 were stimulated with ligands that relatively weakly activated the inflammasome, the cells did not enter pyroptosis but instead secreted IL-12 family cytokines and IL-1β. These cytokines induced prominent T helper type 1 (TH1) and TH17 responses that were superior to those seen in response to Toll-like receptor (TLR) stimulation alone or to stronger, classical inflammasome ligands. These findings not only define the human cDC2 subpopulation as a prime target for the treatment of inflammasome-dependent inflammatory diseases but may also inform new approaches for adjuvant and vaccine development.