ß-1,3-glucan Shaping Natural Killer Cell Immunity

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Natural Killer (NK) cells are one of the first lines of defense among the cellular immune cell system. Unlike adaptive immune cells such as T cells and B cells, NK are historically considered innate immune cells that directly kill pathogens, including bacteria, parasites and fungi, as well as tumor cells and virus-infected cells without prior stimulation. This property is part of natural immunity, and hence the name, natural killer cells. However, recent studies have provided evidence that NK cells acquire enhanced responses to previously encountered pathogen, a property previously ascribed to adaptive immune cells such as T and B cells. NK cells show adaptive immune properties in which prior stimulus causes expansion and persistence of a stimulus (antigen)-specific responsive cell that leads to long term immunity with enhanced efficacy. Several studies demonstrated antigen-specific NK cell memory-like properties in response to the mouse cytomegalovirus (MCMV), herpes simplex virus (HSV), human cytomegalovirus (HCMV), Hepatitis C virus (HCV), hepatitis B virus (HBV), chikungunya virus, or HIV. Most of these studies used whole microorganisms. It is unknown whether fungi, and more specifically, whether any soluble components of the organism induce NK cell adaptive immune memory.******Our previous studies showed that NK cells recognize and directly kill fungi, which requires NK cells to contact the fungal cell and form a conjugate. Recently, we demonstrated that the natural cytotoxicity receptor, NKp30, is the NK cell receptor used to recognize and mediate cytotoxicity against fungi. More recently, we discovered that a polysaccharide, β-1,3-glucan, a component of the fungal cell wall, but also a component of many bacteria and cereals, is the binding partner for NKp30 (Nat. Commun. under revision). In addition, we demonstrated that soluble β-1,3-glucan enhanced subsequent NK cell cytotoxicity against Cryptococcus neoformans and Candida albicans, which are common fungi found in the environment and many diseases. β-1,3-glucan enhanced NKp30 expression and release of cytolytic molecules required for killing of microbes, such as perforin. However, it not known how β-1,3-glucan modulates NK cell immunity and whether this enhanced killing is an adaptive immune response.******In this proposal, we will explore the hypothesis that “β-1,3-glucan can trigger NK cell memory by binding to specific domains of NKp30”. We will first dissect interactions of NKp30 with β-1,3-glucan, and determine the binding sites from both NKp30 and β-1,3-glucan. We will investigate the mechanism and effects of β-1,3-glucan or its binding domain in shaping NK cell immunologic memory. Data derived from these studies will better our understanding whether, and how, a ubiquitous carbohydrate in nature strengthens our immune host defense system.