Hatscher Lukas, Lehmann Christian H K, Purbojo Ariawan, Onderka Constantin, Liang Chunguang, Hartmann Arndt, Cesnjevar Robert, Bruns Heiko, Gross Olaf, Nimmerjahn Falk, Ivanović-Burmazović Ivana, Kunz Meik, Heger Lukas, Dudziak Diana
Laboratory of Dendritic Cell Biology, Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg, 91052 Erlangen, Germany.
Department of Pediatric Cardiac Surgery, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg, 91054 Erlangen, Germany.
Sci Signal. 2021 Apr 27;14(680):eabe1757. doi: 10.1126/scisignal.abe1757.
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 (T1) and T17 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.
树突状细胞（DCs）上的模式识别受体对微生物和危险信号的检测以及随后炎性小体的形成对于启动保护性免疫反应至关重要。尽管炎性小体的激活导致细胞因子IL-1β的分泌通常伴随着焦亡（一种溶解性程序性细胞死亡的炎症形式），但一些细胞可以存活并处于过度激活状态。在这里，我们发现传统2型DC（cDC2）亚群是主要的人类DC亚群，在转录和功能上易于形成炎性小体并做出反应而不发生焦亡。当用相对较弱激活炎性小体的配体刺激cDC2时，细胞不会进入焦亡，而是分泌IL-12家族细胞因子和IL-1β。这些细胞因子诱导了显著的1型辅助性T细胞（T1）和17型辅助性T细胞（T17）反应，这些反应优于单独对Toll样受体（TLR）刺激或更强的经典炎性小体配体的反应。这些发现不仅将人类cDC2亚群定义为治疗炎性小体依赖性炎症性疾病的主要靶点，还可能为佐剂和疫苗开发提供新方法。
