Inflammasome responses and hyperactivation in primary human DC subpopulations
HATSCHER L. 2, KASZUBOWSKI T. 2, AMON L. 2, LEHMANN C. 2, PURBOJO A. 3, ONDERKA C. 4, LIANG C. 5, HARTMANN A. 6, CESNJEVAR R. 7, BRUHNS H. 8, GROSS O. 9, NIMMERJAHN F. 10, IVANOVIC-BURMAZOVIC I. 4, KUNZ M. 11, HEGER L. 2, DUDZIAK D. 1,2
1 Friedrich-Schiller-University Jena, University Hospital Jena, Institute of Immunology, Jena, Germany; 2 Friedrich-Alexander-University Erlangen-Nuernberg, University Hospital Erlangen, Department of Dermatology, Erlangen, Germany; 3 University Hospital Erlangen, Department of Pediatric Cardiac Surgery, Erlangen, Germany; 4 LMU Munich, Chair of Inorganic Chemistry - Bioinorganic Chemistry and Coordination Chemistry, Munich, Germany; 5 University of Wuerzburg, Biocenter, Wuerzburg, Germany; 6 Friedrich-Alexander-University Erlangen-Nuernberg, University Hospital Erlangen, Department of Pathology, Erlangen, Germany; 7 Universitäts-Kinderspital Zuerich, Chair of Heart Surgery, Zuerich, Germany; 8 Friedrich-Alexander-University Erlangen-Nuernberg, University Hospital Erlangen, Medicine 5, Erlangen, Germany; 9 University of Freiburg, Medical Center, Institute of Neuropathology, Freiburg, Germany; 10 Friedrich-Alexander-University Erlangen-Nuernberg, Chair of Genetics, Erlangen, Germany; 11 Friedrich-Alexander-University Erlangen-Nuernberg, Chair of Medical Informatics, Erlangen, Germany
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. Typically, the activation of inflammasomes leads to IL-1beta secretion accompanied by pyroptotic cell death. However, dependent on the cell type and the inflammasome ligands used, some cells can survive inflammasome activation and exist in a state of hyperactivation (defined by IL-1beta secretion from living cells along with other pro-inflammatory cytokines).
Here, we wanted to explore how the inflammasome response is regulated in human primary DC subpopulations.
We performed flow cytometry, cell sorting, T-cell-assays, nanostring, bioinformatic- and CBA-analyses.
We found that the conventional type 2 DC (CD1c+ cDC2) subset is the major human DC-subset that is transcriptionally and functionally able to induce inflammasome formation and enter a state of hyperactivation with secretion of IL-12 family cytokines as well as IL-1beta. Hyperactivated cDC2 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 pyroptosis-inducing inflammasome ligands. Further subsetting of CD1c+ cDC2 into DC2 and DC3 revealed that DC3 generally induced stronger inflammasome responses, which were associated with higher levels of cell death. Although DC2 released lower levels of inflammasome-dependent IL-1beta, they induced stronger CD4+ T cell responses compared to DC3 (predominantly skewed towards TH1/TH17-phenotype).
In conclusion, DC2 and DC3 are capable to enter a state of hyperactivation resulting in enhanced T-cell stimulatory capacity with DC2 being superior to DC3. Our findings may enable new approaches for adjuvant- and vaccine-development.
This project was funded by the German Research Foundation [Deutsche Forschungsgemeinschaft (DFG)] (CRC1181-TPA7-261193037, DU548/5-1, RTG2599-421758891, the Bavarian State Ministry of Science and Art (Bayresq.Net-IRIS) and the Agence Nationale de la Recherche (ANR) and the DFG (DU548/6-1).