Grant: Operating 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 type-1 innate lymphoid cells (ILC) that can detect and eliminate infected, cancer, and transplanted cells. In addition, there are two other major ILC subsets: type-2 ILC, which regulate allergy, especially in the lungs; and type-3 ILC, which regulate normal gut function, including maintenance of intestinal tissue and support for commensal microflora, our 'good' bacteria that help digest food. How NK and ILC cells perform their functions requires understanding of how they develop properly, 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 pathogenic cell. We have identified a receptor-ligand family (NKR-P1:Clr) that contributes to NK cell and ILC immune recognition at the molecular level. Some of these NKR-P1 receptors are inhibitory, so normal cells express the Clr ligands to regulate or prevent NK cell responses ("healthy-self"), while infected and cancerous cells lose Clr expression and are eliminated by NK cells ("missing-self"). This supports a role for the NKR-P1:Clr interactions in fighting cancer and infectious disease. However, malignant cancer cells and viral pathogens can evolve ways to subvert this immunity and become pathogenic. In addition, there are stimulatory NKR-P1 receptors that recognize abnormal proteins and directly activate NK cells ("induced-self"). We propose to advance our understanding of innate immunity by studying how these cells develop, how their function supports our immune defenses in fighting cancer and infection, and how pathogens can evade this immune recognition. This knowledge could lead to therapies in cancer treatment and control of infectious disease.