Investigating the role of Ets1 in natural killer cell terminal maturation and function - Project Summary NK cells are fast-acting, cytotoxic immune cells vital for protecting against herpesviruses and cancer. Given their ability to identify infected and transformed cells in an MHC class I-independent manner, NK cells have become increasingly studied for their potential as off-the-shelf immunotherapies. While NK cells exhibit tremendous potential for future technologies, many strategies have been hindered by our limited knowledge of the factors that guide expansion, terminal maturation, and cytotoxicity. Here, we propose to study how Ets1, a highly conserved and tightly regulated transcription factor in lymphocytes, contributes to mature NK (mNK) cell terminal maturation and function. To address the role of Ets1 in mNK cells, I generated an NK cell-driven Ets1 conditional knockout mouse line (Ets1 cKO, Ncr1Cre Ets1F/F). These mice generate biallelic deletions of Ets1 in mNK cells without affecting other lymphocyte lineages. Preliminary data presented here demonstrate that the loss of Ets1 in undifferentiated mNK cells results in a severe population defect in the bone marrow and spleen with a specific loss of the differentiated, cytotoxic effector subset. To address the role of Ets1 in cytotoxic effector competent mNK cells, I generated a tamoxifen-inducible NK-cell driven knockout mouse line (Ets1 TAM-KO, Ncr1ERT2 Ets1F/F) that efficiently deletes Ets1 in differentiated mNK cells without inducing a maturation block. Preliminary data from these mice suggests that Ets1 is not required for differentiated mNK cell survival, but may limit terminal maturation and cell activation. The goal of this project is to establish the mechanistic role of Ets1 in mNK cells. We propose two aims that will (i) establish how Ets1 promotes the development of undifferentiated mNK cells into the cytotoxic effector subset and (ii) determine how Ets1 expression in differentiated, cytotoxic effector NK cells regulates terminal maturation and function. Accomplishing the proposed studies will illuminate outstanding developmental and functional questions and contribute to the exciting and growing field of NK cell biology. These studies will help detail molecular mechanisms of Ets1 in mNK cells and may inform the design of improved NK cell-based immunotherapies. This project is accompanied by a training plan developed by my mentors and me that delineates several goals needed to propel me toward becoming a successful independent physician-scientist. These goals include gaining expertise in interrogating transcription factor functions in immune cells, refining my skills in bioinformatics, developing proficiency in scientific communication, and integrating my scientific and clinical training. Realizing these goals will equip me with fundamental skills that will support my aspirations to become a physician-scientist oncologist capable of spearheading novel therapeutic avenues.
