Compartmentalized gut lymph node drainage dictates adaptive immune responses
Compartmentalized gut lymph node drainage dictates adaptive immune responses
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DOI：
10.1038/s41586-019-1125-3
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发表时间：
2019-05-02
期刊：
影响因子：
64.8
通讯作者：
Mucida, Daniel
中科院分区：
文献类型：
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作者：
Esterhazy, Daria;Canesso, Maria C. C.;Mucida, Daniel
肠道免疫系统具有一项具有挑战性的任务，即耐受外来营养物质和共生微生物群，同时排除或消除摄入的病原体。这种平衡的失败会导致炎症性肠病、食物过敏和侵袭性胃肠道感染等疾病(1)。因此，多种免疫机制可以维持组织的完整性，包括平衡生成效应T（T- h）细胞和FOXP3（+）调节性T（pT(reg)）细胞，它们分别介导对病原体的抗性和调节过度的免疫激活（1-4）。肠引流淋巴结（gln）是协调对腔内扰动的适应性免疫的关键部位（5-7）。然而，目前尚不清楚它们如何同时支持耐受性和炎症反应。在这里，我们表明gln对它们排泄的功能性肠段具有免疫特异性。基质细胞和树突状细胞的基因特征和T细胞对相同腔内抗原的极化在gln之间是不同的，近端小肠引流gln优先引起耐受性反应，远端gln优先引起促炎T细胞反应。这种分离允许远端gln靶向接种，并在结肠感染期间维持十二指肠pTreg细胞诱导。相反，分区二分法被手术切除部分远端gln和十二指肠感染所扰乱，对淋巴器官和组织免疫反应都有影响。我们的研究结果表明，耐受性和炎症性肠道反应之间的冲突在一定程度上可以通过离散的gLN引流来解决，并鼓励抗原靶向特定的肠道部分进行治疗性免疫调节。
The intestinal immune system has the challenging task of tolerating foreign nutrients and the commensal microbiome, while excluding or eliminating ingested pathogens. Failure of this balance leads to conditions such as inflammatory bowel diseases, food allergies and invasive gastrointestinal infections(1). Multiple immune mechanisms are therefore in place to maintain tissue integrity, including balanced generation of effector T (T-H) cells and FOXP3(+) regulatory T (pT(reg)) cells, which mediate resistance to pathogens and regulate excessive immune activation, respectively(1-4). The gut-draining lymph nodes (gLNs) are key sites for orchestrating adaptive immunity to luminal perturbations(5-7). However, it is unclear how they simultaneously support tolerogenic and inflammatory reactions. Here we show that gLNs are immunologically specific to the functional gut segment that they drain. Stromal and dendritic cell gene signatures and polarization of T cells against the same luminal antigen differ between gLNs, with the proximal small intestine-draining gLNs preferentially giving rise to tolerogenic responses and the distal gLNs to pro-inflammatory T cell responses. This segregation permitted the targeting of distal gLNs for vaccination and the maintenance of duodenal pTreg cell induction during colonic infection. Conversely, the compartmentalized dichotomy was perturbed by surgical removal of select distal gLNs and duodenal infection, with effects on both lymphoid organ and tissue immune responses. Our findings reveal that the conflict between tolerogenic and inflammatory intestinal responses is in part resolved by discrete gLN drainage, and encourage antigen targeting to specific gut segments for therapeutic immune modulation.