瑞士洛桑大学Grégory Verdeil研究团队提出肿瘤微环境中转录因子NFAT5的激活会导致CD8+ T细胞衰竭。这一研究成果发表在2023年9月14日出版的国际学术期刊《自然—免疫学》上。

他们发现NFAT5，一种缺乏AP-1对接位点的NFAT家族转录因子，在慢性感染和肿瘤背景下，在耗尽的CD8+ T细胞中高度表达，但在肿瘤诱导的CD8+ T细胞衰竭中是选择性需要的。在CD8+ T细胞中，NFAT5的过表达降低了肿瘤控制，而NFAT5的缺失通过促进肿瘤特异性CD8+ T细胞的积累来改善肿瘤控制，这些CD8+ T细胞比野生型NFAT5水平的细胞，特别是在前体耗尽的PD-1 +TCF1+ TIM-3-CD8 +T细胞群中，减少了衰竭相关蛋白TOX和PD-1的表达，并产生更多的细胞因子，如IFN α和TNF。

慢性感染淋巴细胞性脉络丛脑膜炎病毒克隆13时，NFAT5不促进T细胞衰竭。NFAT5的表达是由TCR触发诱导的，但其转录活性是肿瘤微环境特异性的，需要高渗透压。因此，NFAT5以肿瘤选择性的方式促进CD8+ T细胞的衰竭。

据了解，在慢性感染或癌症期间持续暴露于抗原会使T细胞功能失调。调节这种衰竭状态的分子机制被认为在感染和癌症中是常见的，尽管它们的微环境存在明显差异。

附：英文原文

Title: Activation of the transcription factor NFAT5 in the tumor microenvironment enforces CD8+ T cell exhaustion

Author: Till, Laure, Cropp, Daniela, Charmoy, Mlanie, Reichenbach, Patrick, Andreatta, Massimo, Wyss, Tania, Bodley, Gabrielle, Crespo, Isaac, Nassiri, Sina, Lourenco, Joao, Leblond, Marine M., Lopez-Rodriguez, Cristina, Speiser, Daniel E., Coukos, George, Irving, Melita, Carmona, Santiago J., Held, Werner, Verdeil, Grgory

Issue&Volume: 2023-09-14

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. Here we found that NFAT5, an NFAT family transcription factor that lacks an AP-1 docking site, was highly expressed in exhausted CD8+ T cells in the context of chronic infections and tumors but was selectively required in tumor-induced CD8+ T cell exhaustion. Overexpression of NFAT5 in CD8+ T cells reduced tumor control, while deletion of NFAT5 improved tumor control by promoting the accumulation of tumor-specific CD8+ T cells that had reduced expression of the exhaustion-associated proteins TOX and PD-1 and produced more cytokines, such as IFN? and TNF, than cells with wild-type levels of NFAT5, specifically in the precursor exhausted PD–1+TCF1+TIM–3–CD8+ T cell population. NFAT5 did not promote T cell exhaustion during chronic infection with clone 13 of lymphocytic choriomeningitis virus. Expression of NFAT5 was induced by TCR triggering, but its transcriptional activity was specific to the tumor microenvironment and required hyperosmolarity. Thus, NFAT5 promoted the exhaustion of CD8+ T cells in a tumor-selective fashion. Verdeil and colleagues show that the transcription factor NFAT5 is selectively required in tumor-induced, but not chronic infection-induced, CD8+ T cell exhaustion, possibly due to the modulation of NFAT5 activation by hyperosmolarity in the tumor environment.

DOI: 10.1038/s41590-023-01614-x

Source: https://www.nature.com/articles/s41590-023-01614-x