NFAT公司
肿瘤微环境
CD8型
生物
细胞毒性T细胞
癌症研究
细胞生物学
免疫系统
免疫学
转录因子
基因
遗传学
体外
作者
Laure Tillé,Daniela Cropp,Gabrielle Bodley,Massimo Andreatta,Mélanie Charmoy,Isaac Crespo-Casajus,Sina Nassiri,João Lourenço,M.M. Leblond,Cristina López-Rodríguez,Daniel E. Speiser,Santiago J. Carmona,Werner Held,Grégory Verdeil
标识
DOI:10.1101/2022.03.15.484422
摘要
Abstract Persistent exposure to antigen during chronic infection or cancer renders T cells dysfunctional. The molecular mechanisms regulating this state of exhaustion are thought to be common in infection and cancer, despite obvious differences in their microenvironments. We discovered that NFAT5, an NFAT family member lacking an AP-1 docking site, is highly expressed in exhausted T cells from murine and human tumors and is a central player in tumor-induced exhaustion. While NFAT5 overexpression reduced tumor control, NFAT5 deletion improved tumor control by promoting the accumulation of tumor-specific CD8+ T cells that expressed less TOX and PD-1 and produced more cytokines particularly among precursor exhausted cells. Conversely, NFAT5 had no effect on chronic infection-induced T cell exhaustion. Mechanistically we found that TCR triggering induced NFAT5 expression and that hyperosmolarity stimulated transcriptional activity of NFAT5. We propose that NFAT5 takes over NFAT1/2 to promote exhaustion specifically in tumor-infiltrating CD8+ T cells.
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