The mechanisms of cytotoxic granule exocytosis underlying hemophagocytic lymphohistiocytosis
University Health Network
Toronto, ON Canada
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There are cells in our body that fight diseases, these are known as immune cells and natural killer (NK) cells and CD8+ T cells are two examples of immune cells. They protect us from disease by releasing molecules which specifically target abnormal cells and invading pathogens in the body. This release process is dependent on a calcium (Ca2+) signal and the help of different players within the immune cells. One important player is a protein called Munc13-4. Mutations in Munc13-4 lead to serious diseases including Familial Hemophagocytic Lymphohistiocytosis 3 (FHL3) disease. Individuals with the disease suffer from reduced release from their NK cells and CD8+ T cells and do not effectively remove diseased cells and pathogens. To compensate, these patients present an uncontrolled number of active immune cells, which eventually damage many vital organs. This strongly suggests the need to understand how Munc13-4 protein and other proteins help the release process in the NK and CD8+ T cells, and how their defects impair the release in a hope to find a better cure against the devastating diseases. We recently found that one of the key roles of Munc13-4 in the release process is to sense the Ca2+ signal that triggers the release (Bin et al., 2018). In this proposal, we will further test our new ideas that 1) an unsuspected key protein, syntaxin-3, plays an important role in the release process; 2) Munc13-4 functions require interaction with syntaxin-3; 3) if we modify Munc13-4 protein to enhance its ability to sense Ca2+, then we can enhance release and make NK and CD8+ T cells better at killing pathogens. By studying the mechanism of the release process, we can develop novel ideas to improve the release from immune cells of FHL patients. Therefore, current and future FHL patients will benefit from new therapeutic procedures that can be developed from the information gained in this study.