Prediction of natural killer cell education and repertoire formation by donor immunogenetics

Natural killer (NK) cells are white blood cells that are part of the immune system, and have not been studied extensively. We do not yet understand how NK cells function because the genes and molecules that control them are very complex, and we are still establishing the tools and computational programs to study this complexity. Our NSERC program aims to understand how genes and molecules control NK cells to make them function differently between people. We are hoping to understand the extent of NK cell diversity, and how a limited number of genes can lead to such dramatic changes in the function of the immune system.

In this NSERC project, we will examine small subset of genes that are involved in NK cell function. For these genes, called KIR3DL1 and HLA-B, we already have good tools and computer programs in place. Therefore, we can use KIR3DL1 and HLA-B as a starting point to understand how NK cells are driven to have different functions. In our first aim, we will categorize NK cells based on their known features, then measure the markers that make them more or less sensitive to become activated. In the next part of our studies, we will use the same categories of NK cells, and study how the cell reacts to stimulation. We can do this by triggering the activating receptors on cell surfaces with different amounts of power, then measuring how the cell responds.

NK cell function differs between people and changes if they are moved to a different person, or they are exposed to a new environment, which is similar to what happens during pregnancy, when a person becomes sick, or during the development of their immune system. By studying these changes, we can understand how NK cells become programmed. I recently showed that we can make NK cells change their functions in a similar way by using a new mouse model. In this NSERC project, we now plan to study the features that control NK cell function by measuring them before and after they have been changed by the new “environment” that we will create by putting them into these mice.

NK cells are highly understudied, but they represent up to 30% of the white blood cells in the human body. We already know that they function differently from other white blood cells, and the studies that propose will help us to understand how genes control their unique function. These experiments are important because they explore a feature of the immune system that we do not understand, guiding us toward a more complete understanding of how the immune system works.