Compartmentalized gut lymph node drainage dictates adaptive immune responses. Compartmentalized gut lymph node drainage dictates adaptive immune responses

Purpose: The intestine's main function is to digest and absorb dietary nutrients, with help from the absorptive epithelium and underlying vasculature and lymphatic system, as well as the microbiome. The intestine also houses the largest immune cell population in the body, tasked with providing resistance to toxins and invading pathogens while maintaining tolerance to dietary and microbial antigens, either by local action or lymphatic trafficking to the gut-draining lymph nodes (gLNs) to mount adaptive responses. While previous studies revealed the drainage map to various gLNs along the murine gut, and described immunological differences between gLNs, the underlying cellular components and the functional consequences of gut segment-specific drainage have not been systematically addressed. We sought to understand how compartmentalized lymphatic drainage of the intestinal milieu contributes to immune responses towards luminal antigens. Results: Here we report that gLNs are immunologically unique according to the functional gut segment they drain. Stromal and dendritic cell gene signatures, as well as adaptive T cell polarization against the same luminal antigen, differed between gLNs along the intestine, the proximal small intestine–draining gLNs preferentially giving rise to tolerogenic and the distal gLNs to pro-inflammatory T cell responses. This compartmentalized dichotomy could be perturbed by duodenal infection, surgical removal of select distal gLNs, dysbiosis, or ectopic antigen delivery, impacting both lymphoid organ and tissue immune responses. Conclusions: Our findings reveal that the conflict between tolerogenic and inflammatory adaptive responses is in part resolved by discrete gLN drainage, and encourage gut segment-specific antigen targeting for therapeutic immune modulation. Overall design: Sorted Dendritic cells from Cecal-Colonic, Duodenum and Ileum Lymph Nodes in four different mice. Sorted Follicular and Lymphatic Endothelial cells from Cecal-Colonic, Duodenum and Ileum Lymph Nodes in three different mice.

研究目的：肠道的核心功能是消化并吸收膳食营养物质，这一过程依赖于吸收上皮、下游脉管与淋巴系统，以及肠道菌群的协同参与。同时，肠道亦是体内免疫细胞丰度最高的组织，其核心任务是抵御毒素与入侵病原体，并通过局部作用或向肠道引流淋巴结（gut-draining lymph nodes，gLNs）进行淋巴迁移以启动适应性免疫应答，维持对膳食抗原与微生物抗原的免疫耐受。既往研究已阐明小鼠肠道向不同gLNs的淋巴引流图谱，并描述了各gLNs间的免疫学差异，但肠道节段特异性引流的潜在细胞基础及其功能后果尚未得到系统性阐释。本研究旨在解析肠道微环境的分区淋巴引流如何介导针对管腔抗原的免疫应答。
研究结果：本研究证实，肠道引流淋巴结的免疫学特性与其引流的肠道功能节段密切相关。沿肠道分布的各gLNs之间，基质细胞与树突状细胞的基因表达特征，以及针对同一管腔抗原的适应性T细胞极化模式均存在显著差异：近端小肠引流的gLNs优先诱导耐受原性T细胞应答，而远端gLNs则倾向于启动促炎性T细胞应答。这种分区性的免疫应答二元性可因十二指肠感染、选择性远端gLNs手术切除、菌群失调或异位抗原递送而被扰乱，进而影响淋巴器官与组织的免疫应答。
研究结论：本研究结果揭示，耐受原性与促炎性适应性免疫应答之间的平衡，可通过离散的肠道引流淋巴结引流模式得到部分调控，该发现为基于肠道节段特异性的抗原靶向治疗性免疫调控提供了理论依据。
实验整体设计：从4只不同小鼠的盲肠结肠淋巴结、十二指肠淋巴结与回肠淋巴结中分选树突状细胞；从3只不同小鼠的盲肠结肠淋巴结、十二指肠淋巴结与回肠淋巴结中分选滤泡细胞与淋巴内皮细胞。