Laboratory of Dendritic Cell Biology, Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, 91052, Erlangen, Germany.
Deutsches Zentrum Immuntherapie, 91054, Erlangen, Germany.
Eur J Immunol. 2023 Sep;53(9):e2250123. doi: 10.1002/eji.202250123. Epub 2023 Mar 14.
Exploiting inflammasome activation in dendritic cells (DCs) is a promising approach to fight cancer and to augment adjuvant-induced immune responses. As inflammasome formation is typically accompanied by pyroptosis, hyperactivation-defined as inflammasome activation in the absence of pyroptosis-represents a mechanism of circumventing cell death of DCs while simultaneously benefitting from inflammasome signaling. We previously demonstrated a unique specialization for inflammasome responses and hyperactivation of human cDC2 among all human DC subsets. As recent investigations revealed heterogeneity among the human cDC2 population, we aimed to analyze whether the two recently identified cDC2 subpopulations DC2 and DC3 harbor similar or different inflammasome characteristics. Here, we report that both DC2 and DC3 are inflammasome competent. We show that DC3 generally induce stronger inflammasome responses, which are associated with higher levels of cell death. Although DC2 release lower levels of inflammasome-dependent IL-1β, they induce stronger CD4 T cell responses than DC3, which are predominantly skewed toward a T 1/T 17 phenotype. Thus, mainly DC2 seem to be able to enter a state of hyperactivation, resulting in enhanced T cell stimulatory capacity.
利用树突状细胞 (DC) 中的炎症小体激活是一种有前途的治疗癌症和增强佐剂诱导免疫反应的方法。由于炎症小体的形成通常伴随着细胞焦亡，超激活——定义为炎症小体激活而没有细胞焦亡——代表了一种规避 DC 细胞死亡的机制，同时又受益于炎症小体信号。我们之前证明了人类 cDC2 在所有人类 DC 亚群中具有独特的炎症小体反应和超激活的专业化。由于最近的研究揭示了人类 cDC2 群体中的异质性，我们旨在分析最近鉴定的两个 cDC2 亚群 DC2 和 DC3 是否具有相似或不同的炎症小体特征。在这里，我们报告说 DC2 和 DC3 都具有炎症小体能力。我们表明，DC3 通常会诱导更强的炎症小体反应，这与更高水平的细胞死亡有关。尽管 DC2 释放的炎症小体依赖性 IL-1β 水平较低，但它们诱导的 CD4 T 细胞反应比 DC3 更强，后者主要偏向 T1/T17 表型。因此，主要是 DC2 似乎能够进入超激活状态，从而增强 T 细胞刺激能力。
