IRF8 is a Key Transcriptional Regulator of IL-2—Induced NK Cell Activation and Antitumor activity 2253333

Abstract Introduction Interleukin-2 (IL-2) promotes Natural killer (NK) cell survival, proliferation, and activation; however its downstream signaling and transcriptional regulators remain incompletely defined. Interferon regulatory factor 8 (IRF8), known for its essential role in dendritic cell and macrophage development, also has not been fully characterized in NK cell—mediated antitumor responses. In this study, we demonstrate that IRF-8 functions is a key transcriptional regulator of IL-2—induced NK cell activation. Methods We generated NK cell—specific IRF-8 knockout mice and evaluated transcriptional and functional changes upon IL-2 stimulation. Results As a result, we observed that IL-2 stimulation translocated IRF8 from the cytoplasm to the nucleus in wild-type NK cells, and also increased the cytotoxicity of NK cells. On the other hand, treatment with IL-2 in IRF-8-deficient NK cells did not induce cytotoxic activation, and the antitumor effect of IL-2 was significantly reduced in a tumor model. Transcriptome analysis confirmed IRF-8-dependent regulation of gene expression in NK cells. Conclusion This study demonstrates that IRF-8 is an essential downstream effector of IL-2 signaling and a central transcriptional regulator of NK cell activation. Funding Source N/A Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)