Natural killer (NK) cells are innate lymphocytes that mediates systemic homeostasis through cytotoxic killing of virus-infected and cancerous cells. To facilitate these processes effectively, NK cell maturation and function is tightly regulated by transcription factors. Growth factor independent 1 (Gfi1) is a transcription factor involved in epigenetic regulation of CD4+ T cells, and ILC2 development and function. Gene expression data previously generated by the lab indicate that Gfi1 is expressed in NK cells but its role has not been explored.
Using Gfi1Tomato reporter mice, we show that Gfi1 is expressed in NK cells and changes in expression parallel NK cell maturation. This lead us to investigate the role of Gfi1 in NK cell maturation and function. We used conditional Gfi1-deficient mice to show that Gfi1 is required to homeostatically maintain mature NK cell numbers at steady-state. Amongst the changes induced in the absence of Gfi1, we found that the transcription factor Eomes failed to be downmodulated. Eomes expression is vital for the development and maintenance of NK cells however, it also needs to be downregulated for complete maturation of NK cells to occur. This suggests that Gfi1 plays a key role in regulating Eomes and other transcription factors to orchestrate a normal NK cell maturation program. Loss of this functional program resulted in Gfi1-deficient mice lacking the ability to protection against the development of tumor metastasis when challenged with the B16F10 melanoma cell line.
Together, these results indicate the importance of Gfi1 in the regulation of NK cell maturation and function. Further studies to identify the mechanism(s) that underpin the Gfi1-driven program will provide insight to regulatory pathways that govern effective NK cell function and may help to develop therapies that harness their effector function in immune protection.