Grant: Project Grant

The innate immune system protects us from pathogenic bacteria, viruses, and cancer, and also helps to maintain normal tissue function at mucosal barriers, such as the skin, gut, and lungs. Natural killer (NK) cells are a subset of innate lymphoid cells (ILC) that possess cytotoxic/killer cell function and can detect/eliminate infected, cancer, and transplanted cells. How NK cells perform these functions requires understanding of the molecules they use to sense what is harmless or dangerous, and how these molecules assist in the decision to ignore a healthy cell, or respond to a diseased cell. We have identified a receptor-ligand family (NKR-P1:Clr) that contributes to NK cell recognition at the molecular level. Some NKR-P1 receptors are inhibitory, so normal cells display "self" Clr ligands to prevent NK cell responses ("healthy-self"), while infected cells lose Clr expression and are killed by NK cells ("missing-self"). This supports a role for NKR-P1:Clr interactions in fighting cancer and infectious disease. However, malignant cancer cells and viral pathogens can evolve ways to subvert innate immunity and become pathogenic, including abnormal display of self ligands, or the evolution of decoy proteins or surrogate "non-self" ligands, respectively. In addition, activating NKR-P1 receptors can recognize some of these abnormal proteins and directly activate NK cells ("induced-self"). We propose to advance our understanding of innate immunity by studying how NK cells use receptors to see "self" ligands, and how viruses use immune evasion proteins to subvert NK detection. Detailed knowledge about how pathogens evade normal immunity, specifically details about how structure-function relationships evolve between host and pathogen, will ultimately lead to advanced therapies in cancer treatment and control of infectious disease, in turn supporting our immune defences to cancer and infection.