Broadening the paradigm of mucosal dendritic cell-mediated induction of gut-homing on T cells.
Broadening the paradigm of mucosal dendritic cell-mediated induction of gut-homing on T cells.
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拓宽了粘膜树突状细胞介导的 T 细胞肠道归巢诱导的范式。
DOI：
10.1053/j.gastro.2014.01.030
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发表时间：
2014
期刊：
影响因子：
29.4
通讯作者：
Rivera-Nieves,Jesús
中科院分区：
文献类型：
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作者：
Collins,ColmB;Rivera-Nieves,Jesús
肠内的稳态由树突状细胞（DC）维持，树突状细胞在先天性免疫和适应性免疫之间的界面处教育T细胞以维持有效的免疫监视和预防过度活跃的免疫应答。在这篇文章中，Ruane等人挑战了肠道DC专门负责向初始T细胞赋予肠道归巢表型的流行范式。研究人员提供了肠外粘膜DC执行类似功能并诱导对肠道病原体的免疫的证据（J Exp Med 2013; 210：1871-1888）。本研究旨在首先评估来自不同器官的DC诱导肠道归巢表型的相对能力。他们最初证明，来自肺和肠系膜淋巴结的DC在卵细胞刺激后诱导OT-II T细胞中的α4β7和CCR 9表达。尽管如前所述，这种功能优先由肠系膜淋巴结中的CD 103 + DC执行，（《实验医学杂志》2005; 202：1063-1073），在肺中，似乎肠道归巢信号的诱导可以响应于CD 11b+或CD 103 + DC而发生，后者与其CD 11b+对应物相比效率较低（以视黄酸[RA]-和转化生长因子β-依赖性方式）。此外，根据唾液酸糖蛋白CD 24（热稳定蛋白）和CD 64（FcγR1）的表达，可将负责诱导该表型的CD 11b+肺DC几乎完全分为CD 11b + CD 24 + CD 64 Neg DC群。这些细胞最近已显示出高度增殖性，表达DC相关抗原和运输至肺引流淋巴结的强能力（Immunity 2013; 38：970-983）。这种肠道归巢分子的异常表达的功能相关性，然后优雅地证明了鼻内致敏卵。这驱动了α4β7在肺和纵隔T细胞上的初始诱导，这在肠组织和引流淋巴结中检测到过继转移细胞频率增加之前。这2个事件的动力学与转移细胞的增殖程度相结合，与α4β7的肠外诱导一致，导致向肠的运输增加。（淋巴细胞从淋巴结排出的抑制剂）进一步证实了转移的细胞在肠中出现之前由肺DC训练的假设，因为FTY 720导致T细胞在纵膈淋巴结中积累，如在先前的实验中所见。这些细胞随后从肠组织中恢复受损。然后，他们通过在白喉毒素敏感（DTR）CD 11 c小鼠中重复这些实验，系统地验证了CD 11b+肺DC在诱导肠道归巢分子响应鼻内激发中的作用
Homeostasis in the intestine is maintained by dendritic cells (DC), which at the interface between innate and adaptive immunity, educate T cells for both the maintenance of effective immune surveillance and for the prevention of overactive immune responses. In this article, Ruane et al challenge the prevailing paradigm that intestinal DC are exclusively responsible for conferring a gut-homing phenotype to naive T cells. The investigators provide evidence that extraintestinal mucosal DCs perform a similar function and induce immunity to intestinal pathogens (J Exp Med 2013; 210: 1871–1888). This study aimed to first assess the relative capacity of DC from various organs to induce a gut-homing phenotype. They initially demonstrated that DC from both the lung and the mesenteric lymph nodes induce α4β7 and CCR9 expression in OT-II T cells after ova stimulation. Although this function was preferentially performed by CD103+ DC in the mesenteric lymph nodes, as has been previously described (J Exp Med 2005; 202: 1063–1073), in the lung it seems that the induction of a gut homing signature can occur in response to either CD11b+ or CD103+ DC, with the latter being less efficient compared with their CD11b+ counterparts (in an retinoic acid [RA]-and transforming growth factor β-dependent manner). Furthermore, the CD11b+ lung DC responsible for inducing this phenotype could be grouped based on their expression of the sialoglycoprotein CD24 (heat-stable protein) and CD64 (FcγR1) almost exclusively into the CD11b+CD24+CD64Neg population of DCs. These cells have been shown recently to be highly proliferative, express DC-associated antigens and a strong capacity to traffic to the lung draining lymph nodes (Immunity 2013; 38: 970–983). A functional relevance for this aberrant expression of gut-homing molecules was then elegantly demonstrated by intranasal sensitization with ova. This drove initial induction of α4β7 on lung and mediastinal T cells, which preceded the detection of increasing frequencies of adoptively transferred cells in intestinal tissues and draining lymph nodes. The kinetics of these 2 events coupled with the degree of proliferation of transferred cells are consistent with the extra-intestinal induction of α4β7 resulting in increased trafficking to the intestine.Blocking T-cell egress with FTY720 (an inhibitor of lymphocyte egress from lymph nodes) lent further credence to the hypothesis that transferred cells are educated by lung DC before their appearance in the intestine, as FTY720 resulted in accumulation of T cells in the mediastinal lymph nodes as seen in the previous experiment. Subsequent recovery of these cells from intestinal tissues was impaired. They then systematically verified the role of CD11b+ lung DC in the induction of gut-homing molecules in response to intranasal challenge by repeating these experiments in diphtheria toxin-sensitive (DTR) CD11c mice