Recent evidence suggests that natural killer (NK) cells can develop immunological memory against viral antigens. Our extensive preliminary data show that cytomegalovirus (CMV) infection is associated with the generation of novel populations of highly differentiated, adaptive NK cells. These NK cell subsets display a genome-wide DNA methylation profile that mirrors that of effector CD8+ T cells. In the present proposal, the applicant (Dr. Frank Cichocki) will study global epigenetic remodeling in CMV-induced adaptive NK cells using a high-throughput sequencing approach and will identify the factors that drive their proliferation and differentiation. Dr. Cichocki has assembled a team of experts from the University of Minnesota's Masonic Cancer Center (MMC) and outside institutions to guide the proposed research activities and provide mentorship during his transition to independence. In addition to direct support from mentors and an advisory committee, Dr. Cichocki will have full access to the shared resources available in the MMC. These include core facilities in flow cytometry, high-throughput sequencing and genomics, biostatistics, and informatics. Dr. Cichocki will continue in his mentored position for two years while analyzing epigenetic remodeling in CMV- induced adaptive NK cells; this work will allow him to gain further expertise in high-throughput sequencing technologies, which will be critical to the success of his future research career. As Dr. Cichocki transitions into the independent phase of his career, he will focus on hypothesis-driven experiments that are based on preliminary data showing that the combination of IL-15, IL-21, IL-12, and CD16 receptor engagement drive the expansion of CMV-induced adaptive NK cells. The data generated from the proposed studies will form the basis for an R01 application to be completed by year 3.5-4. The proposed studies are significant because they address a considerable gap in basic research that is needed to fully characterize adaptive NK cell subsets and understand the mechanisms that drive their differentiation and proliferation before they can be utilized in clinicl settings. These findings may have major clinical implications for the design of CMV vaccines that elicit NK cell memory and in the context of hematopoietic cell transplantation where CMV reactivation is associated with protection from leukemia relapse. Dr. Cichocki's long-term goal is to dedicate his career to advancing basic and translational NK cell biology as an independent investigator at an academic institution. As an immunologist with a deep interest and proven track record in molecular biology and epigenetics, he is in a unique position to answer the questions set forth in this proposal and to rapidly advance the mechanistic understanding of NK cell memory.

Public Health Relevance

More than half of the world's population is infected with cytomegalovirus (CMV) and will remain infected for life. CMV infection can cause abnormal embryonic development during pregnancy or death in newborn children, but surprisingly, it can also help to prevent leukemia relapse after stem cell transplantation. This project investigates the mechanisms by which natural killer (NK) cells develop long-lived and highly specific sensitivity to CMV and the requirements for adaptive NK cell expansion.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Career Transition Award (K99)
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Special Emphasis Panel (MTI (JA))
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Welniak, Lisbeth A
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University of Minnesota Twin Cities
Internal Medicine/Medicine
Schools of Medicine
United States
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Sarhan, Dhifaf; Hippen, Keli L; Lemire, Amanda et al. (2018) Adaptive NK Cells Resist Regulatory T-cell Suppression Driven by IL37. Cancer Immunol Res 6:766-775
Cichocki, Frank; Wu, Cheng-Ying; Zhang, Bin et al. (2018) ARID5B regulates metabolic programming in human adaptive NK cells. J Exp Med 215:2379-2395
Cichocki, Frank; Valamehr, Bahram; Bjordahl, Ryan et al. (2017) GSK3 Inhibition Drives Maturation of NK Cells and Enhances Their Antitumor Activity. Cancer Res 77:5664-5675
Cichocki, Frank; Verneris, Michael R; Cooley, Sarah et al. (2016) The Past, Present, and Future of NK Cells in Hematopoietic Cell Transplantation and Adoptive Transfer. Curr Top Microbiol Immunol 395:225-43