Santosa Endi K, Zhang Jennifer M, Sauter John C, Owyong Mark, Sun Joseph C
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY, United States.
J Immunol. 2025 Jun 1;214(6):1141-1146. doi: 10.1093/jimmun/vkaf041.
Natural killer (NK) cells are innate lymphocytes that exhibit adaptive traits particularly evident during cytomegalovirus (CMV) infection. Following mouse CMV (MCMV) infection, NK cells upregulate the transcription factors IRF4 and IRF8, which are indispensable for their survival and proliferation upon viral infection. However, it is unclear whether these factors are expressed within the same individual cell and whether deficiency in one could be compensated by the other. In this study, we observed that a subset of NK cells co-express high levels of IRF4 and IRF8 in an NFκB-dependent manner. These IRF4HighIRF8High NK cells are specifically enriched for activated but immature cells with high proliferative potential during MCMV infection. Functionally, NK cells lacking both IRF4 and IRF8 develop normally, but experience a more severe expansion defect during virus exposure compared to NK cells deficient in a single factor. Thus, our study reveals a cooperative interplay between IRF4- and IRF8-dependent transcriptional networks in regulating NK-cell antiviral responses.
自然杀伤（NK）细胞是先天性淋巴细胞，在巨细胞病毒（CMV）感染期间表现出特别明显的适应性特征。感染小鼠巨细胞病毒（MCMV）后，NK细胞上调转录因子IRF4和IRF8，这对于它们在病毒感染后的存活和增殖是必不可少的。然而，尚不清楚这些因子是否在同一个体细胞中表达，以及其中一个因子的缺陷是否可以由另一个因子补偿。在本研究中，我们观察到一部分NK细胞以NFκB依赖的方式共表达高水平的IRF4和IRF8。这些IRF4高IRF8高的NK细胞在MCMV感染期间特别富集了具有高增殖潜力的活化但未成熟的细胞。在功能上，同时缺乏IRF4和IRF8的NK细胞发育正常，但与缺乏单一因子的NK细胞相比，在病毒暴露期间经历更严重的扩增缺陷。因此，我们的研究揭示了IRF4和IRF8依赖性转录网络在调节NK细胞抗病毒反应中的协同相互作用。
