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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Differential homing mechanisms regulate regionalized effector CD8αβ~+ T cell accumulation within the small intestine
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Differential homing mechanisms regulate regionalized effector CD8αβ~+ T cell accumulation within the small intestine

机译：差异性归巢机制调节小肠内区域性效应CD8αβ〜+ T细胞的积累

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摘要

The CC chemokine receptor (CCR)9 is expressed on the majority of small intestinal, but few colonic, T cells, whereas its ligand CCL25 is constitutivefy expressed by small intestinal epithelial cells. As such, CCR9/CCL25 have been proposed to play a central role in regulating small intestinal but not colonic immune responses and thus to organize regionalized immunity within the intestinal mucosa. Here, we demonstrate that CCL25 is expressed at reduced levels by epithelial cells in the distal compared with proximal small intestine, which correlated with less efficient CCR9-dependent effector CD8αβ~+ T cell entry into the ileal epithelium. In vitro-generated α_4β_7~+ effector CD8αβ~+ T cell entry into the lamina propria was less dependent on CCR9 than entry into the epithelium along the entire length of the small intestine and in particular in the ileum. CCR9-independent α_4β_7~+ effector CD8αβ~+ T cell entry was pertussis toxin-sensitive, suggesting a role for additional G_(α_1)-linked G protein-coupled receptors. Finally, in vivo-primed effector CD8αβ~+ T cells displayed regionalized differences in their entry to the small intestinal epithelium with enhanced CCR9-independent entry to the ileum. These results highlight a hitherto underappreciated compartmentalization of immune responses within the small intestine and have direct implications for targeting strategies aimed at regulating T cell localization to the small intestinal mucosa.
机译：CC趋化因子受体（CCR）9在大多数小肠上表达，但在结肠T细胞中很少表达，而其配体CCL25在小肠上皮细胞中组成性表达。这样，已经提出CCR9 / CCL25在调节小肠而非结肠免疫应答中起中心作用，从而在肠粘膜内组织区域性免疫。在这里，我们证明与近端小肠相比，CCL25在远端的上皮细胞表达水平降低，这与CCR9依赖性效应CD8αβ+ T细胞进入回肠上皮的效率较低相关。体外产生的α_4β_7〜+效应子CD8αβ〜+ T细胞进入固有层的依赖性较小，而沿着小肠的整个长度（尤其是回肠）进入上皮的依赖性较小。不依赖CCR9的α_4β_7〜+效应子CD8αβ〜+ T细胞进入对百日咳毒素敏感，提示其对其他G_（α_1）连接的G蛋白偶联受体也有作用。最后，体内启动的效应CD8αβ〜+ T细胞在进入小肠上皮细胞方面表现出区域性差异，而与CCR9无关的进入回肠的能力增强。这些结果突显了迄今为止在小肠内免疫反应的区隔不足，并且对旨在调节T细胞在小肠粘膜中定位的靶向策略有直接影响。

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