Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism
Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism
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DOI：
10.1038/nature25437
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发表时间：
2018-02-08
期刊：
影响因子：
64.8
通讯作者：
Germain, Ronald N.
中科院分区：
文献类型：
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作者：
Mao, Kairui;Baptista, Antonio P.;Germain, Ronald N.
哺乳动物肠道内栖息着大量统称为微生物群的微生物，这些微生物与其宿主具有互惠互利的关系(1-3)。通常，肠道微生物群在个体发育过程中成熟到平衡共生状态，其特征是不存在不良炎症(4,5)。先天淋巴细胞 (ILC) 和传统 T 细胞亚群被认为在遏制和清除微生物病原体方面具有冗余功能 (6,7)，但这两个主要淋巴细胞群各自如何促进形成成熟的共生微生物组并帮助维持组织稳态尚未确定。在这里，我们使用先进的多重定量成像方法，在缺乏 CD4(+) T 细胞的小鼠中由白细胞介素 (IL)-23 和 IL-22 诱导的第 3 组 ILC 和肠上皮细胞中发现了广泛且持久的磷酸化 STAT3 特征。相比之下，在具有免疫能力的小鼠中，断奶时微生物定植仅短暂地诱导磷酸化-STAT3激活。当 CD4(+) T 细胞免疫因应对不断扩大的共生负担而发展时，这种早期特征就会消失。生理学上，在缺乏适应性CD4+T细胞活性的情况下，第3组ILC持续产生IL-22，通过降低小肠中脂质转运蛋白的表达，导致宿主脂质代谢受损。这些发现为先天性淋巴细胞和适应性淋巴细胞在正常发育过程中如何按顺序并以不同的方式运作以建立稳态共生和组织代谢稳态提供了新的见解。
The mammalian gut is colonized by numerous microorganisms collectively termed the microbiota, which have a mutually beneficial relationship with their host(1-3). Normally, the gut microbiota matures during ontogeny to a state of balanced commensalism marked by the absence of adverse inflammation(4,5). Subsets of innate lymphoid cells (ILCs) and conventional T cells are considered to have redundant functions in containment and clearance of microbial pathogens(6,7), but how these two major lymphoid-cell populations each contribute to shaping the mature commensal microbiome and help to maintain tissue homeostasis has not been determined. Here we identify, using advanced multiplex quantitative imaging methods, an extensive and persistent phosphorylated-STAT3 signature in group 3 ILCs and intestinal epithelial cells that is induced by interleukin (IL)-23 and IL-22 in mice that lack CD4(+) T cells. By contrast, in immune-competent mice, phosphorylated-STAT3 activation is induced only transiently by microbial colonization at weaning. This early signature is extinguished as CD4(+) T cell immunity develops in response to the expanding commensal burden. Physiologically, the persistent IL-22 production from group 3 ILCs that occurs in the absence of adaptive CD4(+) T-cell activity results in impaired host lipid metabolism by decreasing lipid transporter expression in the small bowel. These findings provide new insights into how innate and adaptive lymphocytes operate sequentially and in distinct ways during normal development to establish steady-state commensalism and tissue metabolic homeostasis.