Division of Biochemistry, Graduate School of Pharmaceutical Science and Faculty of Pharmacy, Keio University, 1-5-30 Shiba Koen, Minato-ku, Tokyo, 105-8512, Japan.
Department of Molecular Systems BioAnalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Cell Mol Life Sci. 2024 Oct 5;81(1):425. doi: 10.1007/s00018-024-05455-1.
Intraepithelial lymphocytes (IELs) reside in the epithelial layer and protect against foreign pathogens, maintaining the epithelial barrier function in the intestine. Interactions between IEL and epithelial cells are required for IELs to function effectively; however, the underlying molecular machinery remains to be elucidated. In this study, we found that intestinal epithelium-specific deficiency of the clathrin adaptor protein (AP)-1B, which regulates basolateral protein sorting, led to a massive reduction in IELs. Quantitative proteomics demonstrated that dozens of proteins, including known IEL-interacting proteins (E-cadherin, butyrophilin-like 2, and plexin B2), were decreased in the basolateral membrane of AP-1B-deficient epithelial cells. Among these proteins, CD166 interacted with CD6 on the surface of induced IEL. CD166 knockdown, using shRNA in intestinal organoid cultures, significantly inhibited IEL recruitment to the epithelial layer. These findings highlight the essential role of AP-1B-mediated basolateral sorting in IEL maintenance and survival within the epithelial layer. This study reveals a novel function of AP-1B in the intestinal immune system.
肠上皮内淋巴细胞 (IEL) 位于上皮层内，可抵御外来病原体，维持肠道上皮屏障功能。IEL 与上皮细胞之间的相互作用对于 IEL 的有效功能至关重要，但潜在的分子机制仍有待阐明。在这项研究中，我们发现，网格蛋白衔接蛋白 (AP)-1B 在上皮细胞中的特异性缺失，会导致 IEL 大量减少，AP-1B 调节基底外侧蛋白的分拣。定量蛋白质组学表明，数十种蛋白质（包括已知的 IEL 相互作用蛋白[E-钙黏蛋白、类粘蛋白 2 和 Plexin B2]）在 AP-1B 缺陷的上皮细胞基底外侧膜中减少。在这些蛋白质中，CD166 与诱导的 IEL 表面的 CD6 相互作用。在肠类器官培养物中使用 shRNA 敲低 CD166，可显著抑制 IEL 募集到上皮层。这些发现强调了 AP-1B 介导的基底外侧分拣在 IEL 维持和在上皮层内生存中的重要作用。本研究揭示了 AP-1B 在肠道免疫系统中的新功能。
