LXR signaling controls homeostatic dendritic cell maturation [scRNAseq]

Depending on how an antigen is perceived, dendritic cells (DCs) mature in an immunogenic or tolerogenic manner, safeguarding the balance between immunity and tolerance. Whereas the pathways driving immunogenic maturation in response to infectious insults are well characterized, the signals driving tolerogenic maturation in homeostasis are still poorly understood. Here we demonstrate that engulfment of apoptotic cells triggers homeostatic maturation of conventional cDC1s in the spleen. This process can be modeled by engulfment of empty, non-adjuvanted lipid nanoparticles (LNPs), is marked by intracellular accumulation of cholesterol, and highly unique to type 1 DCs. Engulfment of apoptotic cells or cholesterol-rich LNPs leads to activation of the LXR pathway driving cellular cholesterol efflux and repression of immunogenic genes. In contrast, simultaneous engagement of TLR3 to mimic viral infection via administration of poly(I:C)-adjuvanted LNPs represses the LXR pathway, thus delaying cellular cholesterol efflux and inducing genes that promote T cell immunity. These data demonstrate how DCs exploit the conserved cellular cholesterol efflux pathway to regulate induction of tolerance or immunity and reveal that administration of non-adjuvanted cholesterol-rich LNPs is a powerful platform for inducing tolerogenic DC maturation. We performed CITE-seq to decipher tolerogenic maturation of wild-type cDC1s within the spleen. Combining the measurement of the transcriptome and the surface epitopes of cDC1s facilitated a detailed analysis of the various stages cDC1s go through during this maturation process.

根据对抗原的识别方式不同，树突状细胞（dendritic cells, DCs）会以免疫原性或耐受原性的方式成熟，以此维系免疫应答与免疫耐受之间的动态平衡。目前针对感染性损伤所诱导的免疫原性成熟通路已有较为充分的研究，但稳态条件下介导耐受原性成熟的信号通路仍有待深入阐明。本研究证实，凋亡细胞的吞噬作用可触发脾脏内经典1型树突状细胞（conventional cDC1s）的稳态成熟过程。该过程可通过吞噬无佐剂的空脂质纳米颗粒（lipid nanoparticles, LNPs）进行体外模拟，其标志性特征为细胞内胆固醇蓄积，且该现象仅特异性存在于1型树突状细胞中。吞噬凋亡细胞或富含胆固醇的脂质纳米颗粒会激活肝X受体（LXR）通路，进而驱动细胞胆固醇外流并抑制免疫原性基因的转录。与之相反，通过联合施用聚肌胞苷酸（poly(I:C)）佐剂的脂质纳米颗粒以模拟病毒感染、同时激活Toll样受体3（TLR3）通路，则会抑制LXR通路，从而延缓细胞胆固醇外流并诱导促进T细胞免疫应答的基因表达。上述研究结果揭示了树突状细胞如何利用保守的细胞胆固醇外流通路来调控免疫耐受或免疫应答的诱导，并证实无佐剂的富含胆固醇脂质纳米颗粒可作为诱导耐受原性树突状细胞成熟的高效技术平台。本研究通过细胞索引转录组和表位测序（CITE-seq）解析了脾脏内野生型经典1型树突状细胞的耐受原性成熟过程。结合转录组检测与树突状细胞表面表位的联合分析，可对该成熟过程中经典1型树突状细胞所经历的各个阶段进行细致解析。