Elucidating the Roles of GATA3 and IL-10 in the Development and Function of Natural Killer Cells During Murine Cytomegalovirus Infection

Abstract

Natural killer (NK) cells are lymphocytes of the innate immune system that exhibit cytotoxic functions against virus-infected cells and cancer cells. To achieve their complete functional capacity, NK cells need to differentiate through several stages of development. The maturation of NK cells is initiated in the bone marrow and is a prerequisite to equip the NK cell with migratory capabilities for the seeding of peripheral organs where they can protect the host. Several transcription factors have been shown to guide NK cell development. In this study, using NK cell-specific Gata3-deficient mice, I demonstrated that the transcription factor GATA3 plays an essential role in NK cell terminal differentiation required for bone marrow egress, resulting in decreased NK cell frequencies in the periphery at the steady-state. Despite the immature phenotype of NK cells in the absence of GATA3, these NK cells displayed enhanced proliferation during murine cytomegalovirus (MCMV) infection, indicating that immature NK cells are a reservoir of highly proliferative cytotoxic cells. Although numerous studies have demonstrated the critical role of NK cells in enhancing inflammatory responses through the production of pro-inflammatory cytokines such as IFNγ and TNFα, few studies have described the regulatory functions of NK cells. Using IL-10-GFP reporter mice, I showed that NK cells are major producers of the anti-inflammatory cytokine IL-10 during the early stages of MCMV infection, prompting further investigation into the contribution of NK cell-derived IL-10 on the inflammatory response against MCMV. Using NK cell-specific Il10-deficient mice, I demonstrated that NK cell-derived IL-10 regulates the function of CD4 and CD8 T cells in a model of sustained infection, and prevents liver damage, suggesting that NK cells produce IL-10 to limit immune-associated pathologies. These studies will advance our understanding of how NK cells develop and mediate their antiviral responses, while preventing host tissue damage.