Dissecting the functional impact of natural killer cell receptor variation in cattle.

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Challenges to the health of an organism are met by the immune system. These challenges can arise from external sources, such as bacteria, viruses, or allergens as well as internal sources such as tumours. Meeting all these challenges is a difficult task and has resulted in a highly complex immune system. Pathogenic invaders are constantly changing in an attempt to avoid immune detection. This in turn drives the immune system, fostering a repetitive cycle of change and adaptation for both the host and pathogen. Diverse receptors expressed on a variety of immune cells are an essential part of this host adaptation. A significant proportion (~5 %) of mammalian genomes is dedicated to the immune system, particularly those immune receptors which form gene clusters and families. Within these families mutation and germ-line recombination creates a source for new genes and new variants of old genes. In fact, immune related genes have diversified more than any other type in mammalian genomes. A distinct set of variable and diverse receptors are expressed on natural killer (NK) cells. NK cells are one of the first responders to pathogens. The magnitude of the NK response subsequently directs how the rest of the immune system responds. NK cells are controlled by some of the most diverse immune receptors identified and are especially important in antiviral immunity. Amongst mammals, cattle have the most diverse NK cell receptor system so far identified. As this system evolved to combat infection, it is essential to examine this system in cattle to understand how these economically crucial animals fight infection. This knowledge will enable applied studies to improve vaccines and breed for disease resistance. This proposal will use information from the cattle genome and high-throughput DNA sequencing technology to completely characterise the NK cell receptor gene families in six Holstein-Friesian dairy cattle. This is an economically important breed in the UK and worldwide. By comparing several animals within this breed we can determine the extent of NK cell receptor diversity. Using knowledge of these receptors, we will determine the molecules that they interact with on infected cells to control NK cell function. This will determine if animals that have dissimilar NK cell receptors are likely to respond differently to infection. Finally, we will infect particular cattle cells that are known to activate NK cells and in turn become activated by NK cells. These will be infected with a known economically important cattle pathogen, bovine herpes virus-1. We will then incubate these infected cells with NK cells that express different NK cell receptor genes. By measuring how these NK cells function and how the infected cells respond, it will be possible to determine if NK cell variation causes different immune responses.Knowledge of how NK cells respond to virus infection depending on their receptors is essential. This fundamental research will allow future examination of how individual animals vary in their response to individual pathogens and vaccination. This will create opportunities to increase the frequency of beneficial genes through genomic selection breeding strategies and more accurately measure how effective vaccines protect animals from pathogen challenge.