Introducing the SLAM family and its neighbours
Immune responses to infections and 'alien' cells like cancer tumours are the result of an intricate web of reactions where binding proteins onto cell receptors sets off waves of cellular and molecular reactions. Cellular communication is mediated in many cases by proteins on the cell surface. To unravel a portion of the molecular cascades in immune response, the 'Regulation of immune responses by CD2, CD244 and related receptors' (CD2 AND CD244) project investigated the family of surface proteins known as CD2 or SLAM. NKs are a prime example of cells that can recognise and destroy viruses and cancer cells and they express many SLAM family receptors. One of the main aims of the project scientists was to elucidate how these proteins induce the NK cell to attack its target. Previous studies by the project scientists at Oxford University showed that one of the SLAM receptors, CD244, can make connections to adaptor proteins (SAP and EAT2) that can then link to enzymes. This way, the researchers postulated that the enzymes at the end of the chain can stimulate NK cells to do their job. Using a human NK cell line and a gene delivery system, lentiviral transduction, the scientists inserted genes that would disrupt the expression of the adaptor proteins and therefore the enzymes that may stimulate NK cell action. Measuring NK activity, using the knock-out mechanisms, results indicate that the SLAM family uses both SAP and EAT2 to induce the killer cells. Interestingly, the disruption of enzyme production reduced production of cytokines, key cell-signalling molecules in the immune response. Produced by NK cells, cytokines such as interferon gamma (IFN-gamma) can enhance the anti-tumour responses of NK cells. Knocking out one of the enzymes, PLC-gamma2, reduced the production of IFN-gamma. However, disrupting the other enzyme PLC-gamma1 or the adaptor proteins was accompanied by an increase in IFN-gamma. Project results therefore indicate that proteins responsible for activating cytotoxic responses may also suppress intercellular communication through other pathways. A promising therapeutic pathway for cancers, particularly lymphomas and leukaemias, is to harness the immune system to eradicate tumours and cancer cells. Uncovering how cell and enzyme actors are interrelated and their modulation will lend a boost to being able to control immune system action against cancer.
