Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
Nat Immunol. 2022 Apr;23(4):556-567. doi: 10.1038/s41590-022-01150-0. Epub 2022 Mar 14.
Natural killer (NK) cells are innate lymphocytes that possess traits of adaptive immunity, such as memory formation. However, the molecular mechanisms by which NK cells persist to form memory cells are not well understood. Using single-cell RNA sequencing, we identified two distinct effector NK cell (NK) populations following mouse cytomegalovirus infection. Ly6C memory precursor (MP) NK cells showed enhanced survival during the contraction phase in a Bcl2-dependent manner, and differentiated into Ly6C memory NK cells. MP NK cells exhibited distinct transcriptional and epigenetic signatures compared with Ly6C NK cells, with a core epigenetic signature shared with MP CD8 T cells enriched in ETS1 and Fli1 DNA-binding motifs. Fli1 was induced by STAT5 signaling ex vivo, and increased levels of the pro-apoptotic factor Bim in early effector NK cells following viral infection. These results suggest that a NK cell-intrinsic checkpoint controlled by the transcription factor Fli1 limits MP NK formation by regulating early effector NK cell fitness during viral infection.
自然杀伤 (NK) 细胞是先天淋巴细胞，具有适应性免疫的特征，例如形成记忆。然而，NK 细胞持续形成记忆细胞的分子机制尚不清楚。通过单细胞 RNA 测序，我们在小鼠巨细胞病毒感染后鉴定出两种不同的效应 NK 细胞 (NK) 群体。Ly6C 记忆前体 (MP) NK 细胞在收缩阶段以 Bcl2 依赖的方式表现出增强的存活能力，并分化为 Ly6C 记忆 NK 细胞。与 Ly6C NK 细胞相比，MP NK 细胞表现出不同的转录和表观遗传特征，与富含 ETS1 和 Fli1 DNA 结合基序的 MP CD8 T 细胞共享核心表观遗传特征。Fli1 由 STAT5 信号体外诱导，病毒感染后早期效应 NK 细胞中促凋亡因子 Bim 的水平增加。这些结果表明，由转录因子 Fli1 控制的 NK 细胞内在检查点通过调节病毒感染期间早期效应 NK 细胞的适应性来限制 MP NK 的形成。
