Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY, USA.
Nat Immunol. 2023 Oct;24(10):1685-1697. doi: 10.1038/s41590-023-01620-z. Epub 2023 Sep 11.
Natural killer (NK) cells are innate cytotoxic lymphocytes with adaptive immune features, including antigen specificity, clonal expansion and memory. As such, NK cells share many transcriptional and epigenetic programs with their adaptive CD8 T cell siblings. Various signals ranging from antigen, co-stimulation and proinflammatory cytokines are required for optimal NK cell responses in mice and humans during virus infection; however, the integration of these signals remains unclear. In this study, we identified that the transcription factor IRF4 integrates signals to coordinate the NK cell response during mouse cytomegalovirus infection. Loss of IRF4 was detrimental to the expansion and differentiation of virus-specific NK cells. This defect was partially attributed to the inability of IRF4-deficient NK cells to uptake nutrients required for survival and memory generation. Altogether, these data suggest that IRF4 is a signal integrator that acts as a secondary metabolic checkpoint to orchestrate the adaptive response of NK cells during viral infection.
自然杀伤 (NK) 细胞是具有适应性免疫特征的先天细胞毒性淋巴细胞，包括抗原特异性、克隆扩增和记忆。因此，NK 细胞与它们的适应性 CD8 T 细胞兄弟姐妹共享许多转录和表观遗传程序。在病毒感染期间，各种信号（包括抗原、共刺激和促炎细胞因子）对于小鼠和人类 NK 细胞的最佳反应是必需的；然而，这些信号的整合仍不清楚。在这项研究中，我们发现转录因子 IRF4 整合信号以协调小鼠巨细胞病毒感染期间的 NK 细胞反应。IRF4 的缺失对病毒特异性 NK 细胞的扩增和分化是有害的。这种缺陷部分归因于缺乏 IRF4 的 NK 细胞无法摄取生存和记忆生成所需的营养物质。总之，这些数据表明 IRF4 是一种信号整合因子，作为二级代谢检查点，在病毒感染期间协调 NK 细胞的适应性反应。
