Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations

Abstract

Stimulator of Interferon Genes (STING) is a cytosolic sensor of cyclic dinucleotides (CDNs). The activation of dendritic cells (DC) via the STING pathway, and their subsequent production of type I interferon (IFN) is considered central to eradicating tumours in mouse models. However, this contribution of STING in preclinical murine studies has not translated into positive outcomes of STING agonists in phase I & II clinical trials. We therefore questioned whether a difference in human DC responses could be critical to the lack of STING agonist efficacy in human settings. This study sought to directly compare mouse and human plasmacytoid DCs and conventional DC subset responses upon STING activation. We found all mouse and human DC subsets were potently activated by STING stimulation. As expected, Type I IFNs were produced by both mouse and human plasmacytoid DCs. However, mouse and human plasmacytoid and conventional DCs all produced type III IFNs (i.e., IFN-λs) in response to STING activation. Of particular interest, all human DCs produced large amounts of IFN-λ1, not expressed in the mouse genome. Furthermore, we also found differential cell death responses upon STING activation, observing rapid ablation of mouse, but not human, plasmacytoid DCs. STING-induced cell death in murine plasmacytoid DCs occurred in a cell-intrinsic manner and involved intrinsic apoptosis. These data highlight discordance between STING IFN and cell death responses in mouse and human DCs and caution against extrapolating STING-mediated events in mouse models to equivalent human outcomes.

A lncRNA identifies Irf8 enhancer element in negative feedback control of dendritic cell differentiation

“…We performed de novo transcript assembly of the RNA-seq data and detected two previously unknown transcripts without coding potential downstream of Irf8 : a pDC specific lncRNA ( Tcons_00190250 ) in the following referred to as lncIrf8 and a cDC1 specific lncRNA ( Tcons_00190258 ; Figure 1A and Figure 1—figure supplement 1 ). lncIrf8 and Tcons_00190258 show the same expression pattern in pDC and cDC1, respectively, in BM and spleen ( Figure 1—figure supplement 3 ), as revealed by reanalyzing scRNA-seq and bulk RNA-seq data ( Pang et al, 2022 ; Rodrigues et al, 2018 ). lncIrf8 is transcribed within an enhancer region located 32 kb downstream of the Irf8 TSS labeled by H3K27ac and H3K4me1 and occupied by DC differentiation-associated TF, such as IRF8 and PU.1 ( Figure 1A and Figure 1—figure supplement 1 ).…”

“…( C ) Gene expression of lncIrf8 and Tcons_00190258 lncRNA in splenic DC subsets in vivo and in DC subsets generated in in vitro BM Flt3L culture. Bulk RNA-seq data of splenic pDC (CD11c int CD317 hi CD11b - ), cDC1 (CD11c hi CD317 low CD8 + CD11b - ), and cDC2 (CD11c hi CD317 low CD8 - CD11b - ) were obtained from GSE188992 ( Pang et al, 2022 ). The bulk RNA-seq data of DC from Flt3L culture are from this study.…”

“…scRNA-seq data were reanalyzed from GSE114313 ( Rodrigues et al, 2018 ). Bulk RNA-seq data of splenic pDC, cDC1 and cDC2 were reanalyzed from GSE188992 ( Pang et al, 2022 ).The sequence of the pDC specific lncRNA ( lncIrf8 identified by RACE PCR) and the cDC1 specific lncRNA ( Tcons_00190258 identified by RNA-seq) has been submitted to GenBank. The GenBank accession numbers for lncIrf8 and Tcons_00190258 are ON134061 and ON134062, respectively.…”

The Human Dendritic Cell Atlas: An integrated transcriptional tool to study human dendritic cell biology

“…As DCs are a rare cell population in human tissues, our understanding of their biology has largely arisen from model organisms, but cross-species comparisons have revealed the distinctiveness of mouse DC subsets from human equivalents. These include the absence of shared expression of subset-defining markers (reviewed by Macri et al, 2018), toll-like receptor 8 (TLR8) mediated responses to single-strand RNA (Heil et al, 2004) and expression of co-stimulatory molecules after stimulator of interferon genes (STING)-dependent activation (Pang et al, 2022). To study DC heterogeneity and complexity in humans, many studies have relied on putative DC isolation from blood.…”

The Human Dendritic Cell Atlas: An Integrated Transcriptional Tool to Study Human Dendritic Cell Biology

“…These include the absence of shared expression of subset-defining markers (reviewed in Ref. 3), TLR8-mediated responses to ssRNA (4), and expression of costimulatory molecules after stimulator of IFN genes (STING)dependent activation (5). To study DC heterogeneity and complexity in humans, many studies have relied on putative DC isolation from blood.…”