NK cells were originally discovered due to their novel ability to recognize and kill tumour cells without having previously encountered these aberrant cells, unlike other lymphocytes such as T and B cells. One of the receptor families on NK cells which have been shown to play an important role in tumour recognition are the Ly49 receptor family. Class I major histocompatibility complex (MHC-I) molecules are expressed on all nucleated cells and function as a marker of a “healthy” cell for NK cells. Ly49 receptor family recognition and binding to the host’s MHC-I molecule will signal to the NK cell not to kill this cell since it is healthy.
Alternatively, in transformed cells, such as those which are virally-infected or cancerous, MHC-I expression is reduced on the cell surface, and so, the NK cell now recognizes this cell as being an unhealthy cell. These cells are killed by the NK cell through various means such as direct cytotoxicity or indirectly through cytokine secretion and recruitment of other immune cells.
My project involves the study of the role of the Ly49 receptor family in cancer immunosurveillance. We observed that NK cells from mice with knocked-down expression of the Ly49 receptor family have defective killing of traditional tumour target cells which lack MHC-I expression in both in vitro [51Cr]-release cytotoxicity assays and in vivo rejection assays. Using different carcinoma models such as oncogene-driven lymphoma and carcinogen-induced sarcoma, we observed that mice with knocked-down expression of the Ly49 receptor family show defective tumour control. Specifically they are prone to earlier cancer development as well as metastatic formation. As well, through the use of antibodies and flow cytometry analysis of tumours isolated from Ly49-knock-down and wildtype mice, it was seen that there is differential expression of MHC-I. This observation suggests that tumours which grow in the knock-down mice are phenotypically different from those in the WT mice due to their altered immune environments which directly affect how these tumours develop. Using our genetic murine model with knocked-down expression of Ly49, we hope to study the role of this receptor family in various cancers and extrapolate these findings to the human functional analogue, killer cell immunoglobulin-like receptor (KIR).