Class Ib MHC-Mediated Immune Interactions Play a Critical Role in Maintaining Mucosal Homeostasis in the Mammalian Large Intestine.
Class Ib MHC-Mediated Immune Interactions Play a Critical Role in Maintaining Mucosal Homeostasis in the Mammalian Large Intestine.
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Ib类MHC介导的免疫相互作用在维持哺乳动物大肠中的粘液稳态中起关键作用。
DOI：
10.4049/immunohorizons.2100090
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发表时间：
2021-12-15
期刊：
影响因子：
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通讯作者：
Kumar V
中科院分区：
文献类型：
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作者：
Dasgupta S;Maricic I;Tang J;Wandro S;Weldon K;Carpenter CS;Eckmann L;Rivera-Nieves J;Sandborn W;Knight R;Dorrestein P;Swafford AD;Kumar V
哺乳动物肠道上皮层(IEL)中的淋巴细胞与固有层中的淋巴细胞相比具有独特的组成。目前对结肠炎症性T细胞亚群，如TCRCD8+αβ+T细胞的作用知之甚少。我们最近描述了富含肝脏的先天类TCRCD8MHC调节性T细胞，部分受非经典αβ分子Qa-1b控制，过继转移时可保护T细胞诱导的结肠炎。在这项研究中，我们发现在炎症期间，TCRCD8+αβααT细胞在结肠IEL中减少，并且在急性结肠炎模型中，它们被激动肽激活导致显著的Qa-1b依赖的保护作用。炎症过程中QA-1b的细胞表达和相应的多肽介导的保护作用的依赖性提示，BATF3依赖的CD103+CD11b−1型常规树突状细胞控制着结肠上皮中αβ+CD8ααT细胞的保护功能。在结肠炎模型中，潜在的屏障保护基因Muc2的表达在给予Qa-1b激动肽后得到增强。值得注意的是，在稳定状态下，在Qa-1b缺乏的情况下，由于整个微生物组和代谢组的急剧变化，代谢粘液的粘蛋白的丰度显著降低，外植体培养中的IL-6增加，对葡聚糖硫酸钠的敏感性增强。最后，在炎症性肠病患者中，我们发现在矽肺中人类白细胞抗原-E上调，这是一种与炎症和生物无反应类似的Qa-1b，表明这种调节机制在跨物种中的重要性。
Lymphocytes within the intestinal epithelial layer (IEL) in mammals have unique composition compared with their counterparts in the lamina propria. Little is known about the role of some of the key colonic IEL subsets, such as TCRαβ+CD8+ T cells, in inflammation. We have recently described liver-enriched innate-like TCRαβ+CD8αα regulatory T cells, partly controlled by the non-classical MHC molecule, Qa-1b, that upon adoptive transfer protect from T cell–induced colitis. In this study, we found that TCRαβ+CD8αα T cells are reduced among the colonic IEL during inflammation, and that their activation with an agonistic peptide leads to significant Qa-1b–dependent protection in an acute model of colitis. Cellular expression of Qa-1b during inflammation and corresponding dependency in peptide-mediated protection suggest that Batf3-dependent CD103+CD11b− type 1 conventional dendritic cells control the protective function of TCRαβ+CD8αα T cells in the colonic epithelium. In the colitis model, expression of the potential barrier-protective gene, Muc2, is enhanced upon administration of a Qa-1b agonistic peptide. Notably, in steady state, the mucin metabolizing Akkermansia muciniphila was found in significantly lower abundance amid a dramatic change in overall microbiome and metabolome, increased IL-6 in explant culture, and enhanced sensitivity to dextran sulfate sodium in Qa-1b deficiency. Finally, in patients with inflammatory bowel disease, we found upregulation of HLA-E, a Qa-1b analog with inflammation and biologic non-response, in silico, suggesting the importance of this regulatory mechanism across species.