Circumventing pyroptosis via hyperactivation shapes superior immune responses of human type 2 dendritic cells compared to type 3 dendritic cells

Abstract

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 TH1/TH17 phenotype. Thus, mainly DC2 seem to be able to enter a state of hyperactivation, resulting in enhanced T cell stimulatory capacity.

Straight to the point: targeted mRNA-delivery to immune cells for improved vaccine design

“…Additionally, a recent investigation proposed another distinction between cDC2 subpopulations. This heterogeneity is characterized by the presence of two distinct subpopulations in human, now known as DC2 and DC3 ( 50 ). Single-cell RNA-seq analysis has revealed that both subpopulations exhibit similar gene expression patterns related to inflammasome signaling under steady-state conditions ( 51 ).…”

“…The T cell responses induced by DC2 are predominantly skewed toward a Th1/Th17 phenotype. Thus, it appears that DC2 subpopulation has the ability to enter a state of hyperactivation, resulting in enhanced T cell stimulatory capabilities ( 50 ). Last, this distinction between DC2 and DC3 in human has also been conversely observed in mice ( 53 ).…”

“…cDC2a and cDC2b have a high level of functional specialization. Indeed, cDC2a cells have a regulatory anti-inflammatory function, while cDC2b cells possess proinflammatory potential (49).…”