Maurice De Sousa Dave, Perkey Eric, Le Corre Laure, Boulet Salix, Gómez Atria Daniela, Allman Anneka, Duval Frédéric, Daudelin Jean-François, Brandstadter Joshua D, Lederer Katlyn, Mezrag Sarah, Odagiu Livia, Ennajimi Myriam, Sarrias Marion, Decaluwe Hélène, Koch Ute, Radtke Freddy, Ludewig Burkhard, Siebel Christian W, Maillard Ivan, Labrecque Nathalie
Maisonneuve-Rosemont Hospital Research Center, University of Montreal , Montreal, Canada.
Institut de Recherches Cliniques de Montréal , Montreal, Canada.
J Exp Med. 2025 May 5;222(5). doi: 10.1084/jem.20231758. Epub 2025 Mar 20.
A better understanding of the mechanisms regulating CD8+ T cell differentiation is essential to develop new strategies to fight infections and cancer. Using genetic mouse models and blocking antibodies, we uncovered cellular and molecular mechanisms by which Notch signaling favors the efficient generation of effector CD8+ T cells. Fibroblastic reticular cells from secondary lymphoid organs, but not dendritic cells, were the dominant source of Notch signals in T cells via Delta-like1/4 ligands within the first 3 days of immune responses to vaccination or infection. Using transcriptional and epigenetic studies, we identified a unique Notch-driven T cell-specific signature. Early Notch signals were associated with chromatin opening in regions occupied by bZIP transcription factors, specifically BATF, known to be important for CD8+ T cell differentiation. Overall, we show that fibroblastic reticular cell niches control the ultimate molecular and functional fate of CD8+ T cells after vaccination or infection through the delivery of early Notch signals.
更好地理解调节CD8 + T细胞分化的机制对于开发对抗感染和癌症的新策略至关重要。利用基因小鼠模型和阻断抗体，我们发现了Notch信号促进效应性CD8 + T细胞高效生成的细胞和分子机制。在对疫苗接种或感染的免疫反应的头3天内，二级淋巴器官中的成纤维网状细胞而非树突状细胞，是通过Delta样1/4配体向T细胞传递Notch信号的主要来源。通过转录和表观遗传学研究，我们确定了一个独特的Notch驱动的T细胞特异性特征。早期Notch信号与bZIP转录因子（特别是已知对CD8 + T细胞分化很重要的BATF）占据的区域中的染色质开放有关。总体而言，我们表明成纤维网状细胞龛通过传递早期Notch信号来控制疫苗接种或感染后CD8 + T细胞的最终分子和功能命运。
