Hatscher et al. showed that resting and activated cDC2s enriched from fresh human blood, spleen, and thymus are the main DCs to respond functionally and transcriptionally to extracellular pathogen-associated molecular patterns (PAMPs) to induce inflammasome sensors, effector caspases, and inflammatory cytokines. NLRP3 and caspase-1 inhibitors reduced cDC2 inflammasome activation. Weak, unlike strong, inflammasome activators did not induce death of cDC2s, but provoked them to secrete IL-1β, IL-12p40, and IL-23, which induced greater TH1 and TH17 cell responses than those induced by strong inflammasome or only TLR stimulation.
Contributed by Paula Hochman
ABSTRACT: 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-1_ 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-1_. These cytokines induced prominent T helper type 1 (T(H)1) and T(H)17 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.
Author Info: (1) Laboratory of Dendritic Cell Biology, Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nrnberg, 91052 Erlangen, Germany. (2)
Author Info: (1) Laboratory of Dendritic Cell Biology, Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nrnberg, 91052 Erlangen, Germany. (2) Laboratory of Dendritic Cell Biology, Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nrnberg, 91052 Erlangen, Germany. (3) Department of Pediatric Cardiac Surgery, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nrnberg, 91054 Erlangen, Germany. (4) Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nrnberg, 91058 Erlangen, Germany. (5) Chair of Medical Informatics, Friedrich-Alexander University Erlangen-Nrnberg, 91058 Erlangen, Germany. (6) Department of Pathology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nrnberg, 91054 Erlangen, Germany. (7) Department of Pediatric Cardiac Surgery, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nrnberg, 91054 Erlangen, Germany. (8) Department of Internal Medicine 5-Hematology/Oncology, Friedrich-Alexander University Erlangen-Nrnberg, 91054 Erlangen, Germany. (9) Institute of Neuropathology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany. Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany. Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany. (10) Institute of Genetics, Department of Biology, Friedrich-Alexander University Erlangen-Nrnberg (FAU), 91058 Erlangen, Germany. (11) Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nrnberg, 91058 Erlangen, Germany. Department Chemistry, Ludwigs Maximilians University, 81377 Munich, Germany. (12) Chair of Medical Informatics, Friedrich-Alexander University Erlangen-Nrnberg, 91058 Erlangen, Germany. (13) Laboratory of Dendritic Cell Biology, Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nrnberg, 91052 Erlangen, Germany. (14) Laboratory of Dendritic Cell Biology, Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nrnberg, 91052 Erlangen, Germany. diana.dudziak@uk-erlangen.de. Institute of Genetics, Department of Biology, Friedrich-Alexander University Erlangen-Nrnberg (FAU), 91058 Erlangen, Germany. Deutsches Zentrum Immuntherapie, 91054 Erlangen, Germany. Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg, 91054 Erlangen, Germany. Medical Immunology Campus Erlangen, 91054 Erlangen, Germany.
