Role of Frizzled 5 in NK cell development and antiviral host immunity

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PROJECT SUMMARY 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 transcriptional control of their development and optimal antiviral response remains unclear. Given the shared characteristics between NK cells and CD8+ T cells and that Wnt signaling in CD8+ T cells is instrumental for survival and in mediating responses against pathogens, I postulate that Wnt signaling plays an essential role in NK cell survival and antiviral function. However, the role of Wnt signaling in NK cells is largely unexplored. Thus, this proposal seeks to explore 1) how Wnt signaling is mediated in NK cells, 2) what Wnt ligands are modulating NK cells and what is the source of these ligands, and 3) what are the molecular events orchestrated by Wnt signaling in NK cells during development and host antiviral defense. While profiling the Frizzled (Fzd) family of receptors that bind to Wnt ligands, I found that Fzd5 is prominently and exclusively expressed on NK cells compared to other immune cells. To investigate the role of Fzd5 in NK cells, I generated a novel transgenic mouse containing NK cell-specific deletion of Fzd5. In preliminary data, Fzd5-deficient mice had diminished NK cell numbers and, strikingly, in a mixed bone marrow chimera, Fzd5-deficient NK cells were less capable of repopulating mice compared to wildtype NK cells. Additionally, Fzd5 is essential for proper antigen-specific clonal expansion of NK cells in response to MCMV infection. In Specific Aim 1 I will identify the downstream mediators of Fzd5 signaling and identify the Wnt ligand that binds to Fzd5 on NK cells. In Specific Aim 2 I will investigate the molecular mechanism of Wnt signaling in NK cell antiviral responses. At the completion of this F31 we will gain key insights into the complex transcriptional networks that are induced by Fzd5. 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.