Hayama Mio, Ishii Hiroto, Miyauchi Maki, Yoshida Masaki, Hagiwara Naho, Muramtatu Wataru, Namiki Kano, Endo Rin, Miyao Takahisa, Akiyama Nobuko, Akiyama Taishin
Laboratory for Immune Homeostasis, RIKEN Center of Integrative Medical Sciences, Yokohama, Japan.
Immunobiology, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan.
Front Immunol. 2024 Nov 29;15:1500908. doi: 10.3389/fimmu.2024.1500908. eCollection 2024.
Medullary thymic epithelial cells (mTECs) play a crucial role in suppressing the onset of autoimmunity by eliminating autoreactive T cells and promoting the development of regulatory T cells in the thymus. Although mTECs undergo turnover in adults, the molecular mechanisms behind this process remain unclear. This study describes the direct and indirect roles of receptor activator of NF-κB (RANK) and CD40 signaling in TECs in the adult thymus. Flow cytometric and single-cell RNA-seq (scRNA-seq) analyses suggest that the depletion of both RANK and CD40 signaling inhibits mTEC differentiation from CCL21 mTEC progenitors to transit-amplifying TECs in the adult thymus. Unexpectedly, this depletion also exerts indirect effects on the gene expression of TEC progenitors and cortical TECs. Additionally, the expression levels of AP-1 genes, which enable the further subdivision of TEC progenitors, are up-regulated following the depletion of RANK and CD40 signaling. Overall, our data propose that RANK and CD40 signaling cooperatively maintain mature mTEC frequency in the adult thymus and sustain the characteristics of TEC progenitors through an indirect mechanism.
髓质胸腺上皮细胞（mTECs）在通过消除自身反应性T细胞和促进胸腺中调节性T细胞的发育来抑制自身免疫的发作中起关键作用。尽管mTECs在成体中会发生更新，但这一过程背后的分子机制仍不清楚。本研究描述了核因子κB受体激活剂（RANK）和CD40信号在成年胸腺TECs中的直接和间接作用。流式细胞术和单细胞RNA测序（scRNA-seq）分析表明，RANK和CD40信号的缺失均抑制成年胸腺中CCL21 mTEC祖细胞向过渡扩增TECs的mTEC分化。出乎意料的是，这种缺失也对TEC祖细胞和皮质TECs的基因表达产生间接影响。此外，RANK和CD40信号缺失后，能够进一步细分TEC祖细胞的AP-1基因的表达水平上调。总体而言，我们的数据表明，RANK和CD40信号协同维持成年胸腺中成熟mTEC的频率，并通过间接机制维持TEC祖细胞的特征。
