Role of Arid1a in NK cell development and antiviral immunity

Natural killer (NK) cells have been shown to play a dominant role in the immune-mediated control of viral infection in both humans and mice. Individuals lacking NK cells or NK cell function succumb to fatal viral infections, such as human cytomegalovirus (HCMV). Similarly neonatal mice, which lack mature peripheral NK cells, and adult mice with NK cell deficiencies are extremely susceptible to murine cytomegalovirus (MCMV) infection. Given the clinical significance of HCMV, MCMV infection in mice represents an appropriate model to study NK cell-mediated antiviral immunity. While NK cells are members of the innate immune system, it is now appreciated that NK cells share many characteristics with CD8+ T cells and can exhibit features of adaptive immunity. Although our understanding of the innate and adaptive features of NK cells has increased in the past decade, the molecular and dynamic genomic organization which underlies their development and optimal antiviral response remains unclear. Given the shared characteristics between NK cells and CD8+ T cells and that Arid1a chromatin remodeling in CD8+ T cells is instrumental for antigen-specific proliferation and mediating responses against pathogens, I postulate that Arid1a plays an essential role in NK cell development and antiviral function. However, the role of Arid1a signaling in NK cells is largely unexplored. Thus, this proposal seeks to explore 1) how Arid1a chromatin remodeling is mediated in NK cells for proper NK cell identity, 2) how Arid1a modulates dynamic chromatin organization in NK cells to sustain host antiviral defense. While profiling developing and mature NK cell subsets, I found that Arid1a is highly expressed. To investigate the role of Arid1a in NK cells, I generated a novel transgenic mouse containing NK cell-specific deletion of Arid1a. In preliminary data, one copy loss of Arid1a had diminished NK cell antigen-specific proliferation to MCMV. In Specific Aim 1 I will uncover the role of Arid1a in NK cell development. In Specific Aim 2 I will investigate the molecular mechanism of Arid1a signaling in NK cell antiviral responses. At the completion of this F31 we will gain key insights into the complex molecular networks that are induced by Arid1a. The mechanistic insights derived from this study will be instrumental in the development of novel therapies that enhance NK cell function and influence strategies aimed at improving antiviral therapies. Project Number: 1F31AI191721-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Mariah Lee | Institution: SLOAN-KETTERING INST CAN RESEARCH, NEW YORK, NY | Award Amount: $46,564 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F07C-H (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F31AI19172101A1