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IRF4 阻碍人类 CD8 T 细胞功能,促进细胞增殖和 PD-1 表达

Thibault Hirsch¹, Damien Neyens¹, Céline Duhamel¹

¹De Duve Institute, Université Catholique de Louvain, Brussels, Belgium.

|June 29, 2024

概括

干扰素调节因子4 (IRF4) 通过促进PD-1表达和损害效应因子功能,驱动人类CD8瘤透淋巴细胞 (TILs) 的疲劳. 这清楚地表明IRF4+的TIL是真正耗尽的,而不仅仅是激活的.

科学领域:

免疫学免疫学免疫学
癌症生物学癌症生物学
T细胞生物学T细胞生物学

背景情况:

人类CD8瘤透淋巴细胞 (TILs) 显示受损的效应器功能和PD-1表达通常被归类为耗尽的.
然而,TILs中的这些枯竭性特征可能来自T细胞激活,而不是真正的T细胞枯竭.

研究的目的:

调查转录因子干扰素调节因子4 (IRF4) 在CD8 TIL耗尽中的作用.
在TILs中区分激活诱导的表型和真正的枯竭.

主要方法:

利用CRISPR-Cas9和lentiviral在非癌症捐赠者的CD8T细胞中的过度表达.
分析了与核因子kB (NF-kB) 相关的转录因子活性,细胞增殖,PD-1表达,效应函数和基因表达.
将TIL与来自COVID-19患者的激活T细胞进行比较.

主要成果:

TCR诱导的IRF4促进CD8T细胞的增殖和PD-1表达,同时阻碍效应因子功能和NF-κB调节的基因表达.
减少干扰素γ (IFNγ) 生产的CD8TIL显示激活标记 (IRF4,CD137) 和耗尽标记 (TOX,PD-1).
在COVID-19患者中,激活的T细胞不会表现出高的TOX和PD-1水平,这将它们与耗尽的TIL区分开来.

结论:

在TILs中IRF4上调导致疲劳,其特征是PD-1表达,减少IFNγ产生和活跃循环.
这些发现证实IRF4+ TILs确实已经耗尽,而不仅仅是激活.
IRF4在调节PD-1表达,IFNγ产生和TILs活化后细胞循环中起着至关重要的作用.

关键词:

在 CD8 T 细胞中.CP: 免疫学免疫学在 IRF4 里,你会看到 IRF4.在 NFAT NFAT 中.在PD-1中使用PD-1.这就是TILs.托克斯 (TOX) 是一种毒素.功能障碍功能障碍功能障碍功能障碍疲疲疲疲疲它们的扩散和扩散.瘤是一个瘤.

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