Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
Division of Immunobiology, Department of Medical Life Science, Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan.
J Exp Med. 2018 Feb 5;215(2):501-519. doi: 10.1084/jem.20160659. Epub 2018 Jan 16.
M cells are located in the follicle-associated epithelium (FAE) that covers Peyer's patches (PPs) and are responsible for the uptake of intestinal antigens. The differentiation of M cells is initiated by receptor activator of NF-κB. However, the intracellular pathways involved in M cell differentiation are still elusive. In this study, we demonstrate that the NF-κB pathway activated by RANK is essential for M cell differentiation using in vitro organoid culture. Overexpression of NF-κB transcription factors enhances the expression of M cell-associated molecules but is not sufficient to complete M cell differentiation. Furthermore, we evaluated the requirement for tumor necrosis factor receptor-associated factor 6 (TRAF6). Conditional deletion of TRAF6 in the intestinal epithelium causes a complete loss of M cells in PPs, resulting in impaired antigen uptake into PPs. In addition, the expression of FAE-associated genes is almost silenced in TRAF6-deficient mice. This study thus demonstrates the crucial role of TRAF6-mediated NF-κB signaling in the development of M cells and FAE.
M 细胞位于覆盖派尔集合淋巴结（PPs）的滤泡相关上皮（FAE）中，负责摄取肠道抗原。M 细胞的分化由 NF-κB 受体激活物（RANK）启动。然而，M 细胞分化涉及的细胞内途径仍不清楚。在这项研究中，我们使用体外类器官培养证明了 RANK 激活的 NF-κB 途径对于 M 细胞分化是必不可少的。NF-κB 转录因子的过表达增强了 M 细胞相关分子的表达，但不足以完成 M 细胞分化。此外，我们评估了肿瘤坏死因子受体相关因子 6（TRAF6）的需求。肠上皮细胞中 TRAF6 的条件性缺失导致 PPs 中 M 细胞完全缺失，从而导致抗原摄取到 PPs 受损。此外，TRAF6 缺陷小鼠中 FAE 相关基因的表达几乎被沉默。因此，这项研究表明 TRAF6 介导的 NF-κB 信号在 M 细胞和 FAE 的发育中起着关键作用。
