It is increasingly clear that physico-chemical dysregulation of epithelial cells leads to the upregulation of stress-antigens that make the cells visible to sets of lymphocytes that include gamma delta T cells and NK cells. This form of stress-surveillance can make significant contributions to tumour immunology; transplant rejection; and inflammatory diseases. A central molecular axis underpinning stress-surveillance is the recognition of stress-regulated MHC-I-related molecules, such as MICA and ULBP, by the activating receptor NKG2D. Provocatively, MICA is highly polymorphic, with genetic associations with inflammatory diseases, transplant rejection, and cancer. However, there have been no functional studies of MICA polymorphism. This study will assay the capacity of different MICA alleles and another NKG2D ligand (ULBP2) to activate T cells and NK cells from patients and healthy controls. Building on preliminary data that there is substantial individual variation in the response to different ligands and ligand alleles, this study will use a novel experimental system to investigate and characterise the molecules that regulate this form of immune response. A better knowledge of the functional implications of MICA polymorphisms can provide insight into a large variety of pathologies, and the mechanisms used by viruses or tumour cells to evade stress-induced immune responses. The study may also identify novel regulators of unconventional T cells and NK cells, with both biologic and clinical implications.
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