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细胞位于卵泡相关上皮（FAE）中，该上皮覆盖Peyer斑块（PPs），并负责肠道抗原的摄取。M细胞的分化是由NF-κB受体激活剂引发的。但是，参与M细胞分化的细胞内途径仍然难以捉摸。在这项研究中，我们证明了由RANK激活的NF-κB通路对于使用体外类器官培养的M细胞分化必不可少。NF-κB转录因子的过度表达可增强M细胞相关分子的表达，但不足以完成M细胞分化。此外，我们评估了对肿瘤坏死因子受体相关因子6（TRAF6）的需求。肠道上皮细胞中TRAF6的有条件缺失会导致PP中M细胞的完全丧失，导致PP中抗原吸收受损。另外，在TRAF6缺陷型小鼠中，FAE相关基因的表达几乎被沉默。因此，这项研究证明了TRAF6介导的NF-κB信号传导在M细胞和FAE发育中的关键作用。