Chronic excess IL-18 has ben well associated with autoimmune disease like SJIA, particularity the development of Macrophage Activation Syndrome. Children who are diagnosed with these diseases are known to often have dysregulation of their cytotoxic cells: CD8+ T cells, Natural Killer cells Innate Lymphoid Cells. In my project we want to understand the effect what happens to NK cells and ILCs when they are exposed to high levels of IL-18. We know that the IL-18 receptor is down-regulated in these innate cells but we do not know how they are contributors to the disease phenotype. To test the effect of chronic exposure to IL-18 we used a IL-18 dependent bacterial clearance model, using Chromobacterium violaceum. NK cells need to respond to IL-18 released by macrophages to release perforin which will go on to kill the infected hepatocytes. In the first iteration of using this model to test whether IL-18 transgenic mice(high IL-18) can clear this bacterium as well as wildtype or worse than the positive control (perforin deficient mice), we find that IL-18 high mice clear better than wildtype. This points us to question if IL-18 is increasing cytotoxicity in the Natural killer cells that are chronically exposed. Future experiments include looking at cytotoxicity on the cell-cell basis in a in vitro killing assay using YAC-1 lymphoma cells as a target and NK cells from model mice as effectors.
We may find that overexposed NK cells may be key contributors to the pro-inflammatory phenotype we see in MAS patients.