Natural Killer Cell Immunity Induced by ß-1,3-Glucan

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The immune system has developed to maintain homeostasis while protecting the host from infectious microorganisms. It is now clear that environmental factors activate and shape immunity. ß-1,3-glucan is one such molecule that is both inhaled and consumed in dietary grains and microbes. Evidence shows that dietary ß-1,3-glucan activates immunity including natural killer (NK) cells; however, the mechanisms and their role in host defense development is unknown. The goal of this proposal is to understand how ß-1,3-glucan modulates and causes differentiation of NK cell immunity. Natural Killer (NK) cells are innate lymphocytes that directly kill pathogenic microorganisms, e.g., bacteria, parasites and fungi as well as tumor cells and virus-infected cells without prior stimulation. However, recent studies demonstrate that they can develop a memory-like property similar to adaptive immune cells such as T cells. Adaptive immune cells demonstrate enhanced responses to previously encountered pathogens that enhances their ability to clear invading microbial pathogens. We previously showed that NK cells directly kill Cryptococcus and Candida, environmental fungi that have the ability to disrupt homeostasis and cause pathology. Recently we determined that NKp30 is the NK cell pattern recognition receptor (PRR) that recognizes and mediates NK cell cytotoxicity against these fungi. Furthermore, we identified that ß-1,3-glucan, a pathogen-associated molecular pattern (PAMP) in the fungal cell wall is the ligand for NKp30, which mediates NK cell recognition and killing. Interestingly, we found that ß-1,3-glucan is not only critical for PRR-PAMP-mediated NK cell killing, but also able to enhance NK cell cytotoxicity against C. neoformans and C. albicans. Further experiments suggest that the ß-1,3-glucan-enhanced killing tapers off over few weeks after initial simulation and then showed greater NK cell killing at the fourth week, a similar phenomenon to adaptive immune recall responses. It remains unknown how ß-1,3-glucan enhances NK cell killing and whether it leads to an activation event, a differentiation event, or acquisition of memory that modulates NK cell immunity. In this proposal, we plan to use transgenic and/or humanized mice to determine whether ß-1,3-glucan enhances NK cell cytotoxicity and understand the NKp30 interaction with ß-1,3-glucan in the enhanced NK cell cytotoxicity. We will profile differential gene expression of NK cells in the ß-1,3-glucan-enhanced cytotoxicity using RNA-seq and mass cytometry. The ultimate goal of this program is to understand the mechanisms that ß-1,3-glucan-enhanced killing, and whether ß-1,3-glucan induces antigen specific NK cell clonal expansion and memory development or epigenetic change leading to enhanced NK cell cytotoxicity, and determine whether the enhanced NK cell cytotoxicity is specific to fungi or to a wider range of pathogenic microorganisms.