Identification of antigen-presenting cell-T cell interactions driving immune responses to food

The intestinal immune system must concomitantly tolerate food and commensals and protect against pathogens. Antigen-presenting cells (APCs) orchestrate these immune responses by presenting luminal antigens to CD4+ T cells and inducing their differentiation into regulatory (pTreg) or inflammatory (Th) subsets. Here, we used LIPSTIC to identify APCs that presented dietary antigens under tolerizing and inflammatory conditions. We show that helminth infections disrupted tolerance proportionally to the reduction in ratio between tolerogenic, including migratory cDC1s and Ror?t+ APCs, and inflammatory APCs, represented primarily by cDC2 subsets. However, the inflammatory subset of cDC2s expanded by helminth infection did not present dietary antigens, thus avoiding diet-specific TH2 cell differentiation. Our data uncover cellular mechanisms by which tolerance to food is induced and can be disrupted by infection. Overall design: DCs from duodenal gut-draining lymph nodes (D-gLNs) of mice under steady-state and helminth-infected conditions were analyzed by bulk RNA-seq. Single-cell RNA-seq (SmartSeq2) was performed on individual DCs from D-gLNs of steady-state and helminth-infected mice. DCs from the lamina propria of the duodenum in steady-state and helminth-infected mice were analyzed using 10x Genomics single-cell RNA-seq.

肠道免疫系统需同时耐受食物抗原与共生菌群，同时抵御病原体侵袭。抗原呈递细胞（antigen-presenting cells, APCs）通过将肠腔抗原呈递给CD4+ T细胞，并诱导其分化为调节性（外周调节性T细胞，pTreg）或炎症性（辅助性T细胞，Th）亚群，以协调此类免疫应答。本研究利用LIPSTIC技术，鉴定出在免疫耐受诱导与炎症条件下呈递膳食抗原的抗原呈递细胞。研究发现，蠕虫感染可按比例破坏食物免疫耐受，其破坏程度与致耐受型APCs（包括迁移性cDC1s与RORγt+ APCs）和炎症型APCs（主要以cDC2亚群为代表）的比值降低呈正相关。不过，蠕虫感染扩增的cDC2炎症亚群并不会呈递膳食抗原，因此避免了饮食特异性TH2细胞的分化。本研究揭示了诱导食物耐受并可被感染破坏的细胞机制。整体实验设计：分别对稳态及蠕虫感染状态下小鼠十二指肠引流淋巴结（D-gLNs）中的树突状细胞（DCs）进行批量RNA测序分析；对稳态及蠕虫感染小鼠的十二指肠引流淋巴结内的单个树突状细胞开展单细胞RNA测序（SmartSeq2）；采用10x Genomics单细胞RNA测序技术，分析稳态及蠕虫感染小鼠十二指肠固有层中的树突状细胞。