Grant: Operating Grant

The innate immune system protects us from bacteria, viruses, and cancer. Natural killer (NK) cells are innate immune cells that can detect and destroy infected and tumour cells. How NK cells do this requires understanding of the molecules they use to sense what is harmless or dangerous, and how these molecules assist in the decision to ignore or kill the diseased cell. We have identified a receptor on NK cells, called NKR-P1B, that binds to a protein, named Clrb, on all other cells. Because the NKR-P1B receptor turns off NK cells, normal cells display the "self" Clrb protein to prevent NK cell attack, while infected and cancerous cells lose Clrb protein ("non-self") and are eliminated by NK cells. On the other hand, NKG2D is a different receptor that turns on NK cells. NKG2D binds to "danger" proteins displayed on infected and tumour cells, but not normal cells, and these "danger" flags alert the immune system and NK cells that something is wrong. The combination of receptors that either turn off or turn on NK cells provides a sensitive balance to allow NK cells to discriminate between "good" and "bad" cells. It also suggests a role for multiple NK cell receptors allowing NK cells to fight cancer and infectious disease. I propose to advance our understanding of the role of NK cells in disease, cancer, and infection by studying how NK cells "see" diseased cells. This proposal will study how NK cells use their receptors to interpret levels of different good or bad proteins, what makes these proteins go up or down on diseased cells, and how infectious pathogens or malignant tumour cells can escape this immune recognition. This knowledge could lead to therapies in cancer treatment and vaccines to control infectious disease.