Pathogens are constantly evolving to evade and subvert the immune response. This creates pressure on the immune system to respond and counter evolve to remain effective. This arms race has driven the expansion and diversification of many genes that control the immune response. Such diversity is often variable within a population and species-specific, reflecting the enormous impact of pathogen selection and the need to maintain immune variety.
Natural killer (NK) cell receptors gene families are some of the most diverse genes discovered. Moreover, distinct families have independently diversified in different mammalian groups. These receptors control the function of NK cells, a critical component of the innate immune response. NK cells are lymphocytes of the innate immune system that recognise and respond to infected or transformed cells. This response is crucial for survival as humans lacking functional NK cells succumb to overwhelming viral infection despite possessing an entirely functional adaptive immune system. Livestock viral infections, such as foot-and-mouth disease and bluetongue virus are a major problem in the UK and worldwide. They cause major impact on animal health and welfare and consequently cause considerable economic loss and risks to food security. A better understanding of the immune system and differential disease resistance is a crucial tool to counter these problems.
Our recent studies have revealed that cattle have expanded a novel NK cell receptor gene family, KIR3DX, to produce variation in their NK cell response. In addition, we found that the related and linked leukocyte immunoglobulin-like receptor (LILR) genes have also undergone unique recombination. Both these receptors are located within the cattle leukocyte receptor complex (LRC) gene cluster. Our work is currently focused on fully characterising the LRC NK cell receptor genes of cattle and other domesticated and wild ruminant species from genome to function, and identifying their role in the antiviral immune response. This will lead to better livestock breeding strategies that select for disease resistance and novel disease prevention strategies.
The evolution of ruminant KIR genes
Our analysis has revealed that during ruminant speciation positive selection has produced considerable KIR variation between different species. Ruminants are a group of mammals that have been evolving independently for over 50 million years. Domestication and inbreeding have the potential to reduce this genetic variability by removing distinct genotypes from the breeding population. We are working with London and Whipsnade Zoos through the Zoology Society of London, Edinburgh Zoo through the Royal Zoological Society of Scotland, and the Arizona Game and Fish Department to study the KIR genes of species from several ruminant lineages. This will reveal how and when this fundamental immune component evolved, identify functionally conserved and diversified elements and reveal the KIR that have been under the greatest pathogen selection. As wild relatives of domesticated species will not have endured artificial selection, we shall also be able determine if selection has reduced genetic diversity in cattle and how this impacts NK cell function.
The diversity of cattle KIR
Polymorphism and haplotype variation is a key functional component of NK cell receptors in other mammals. We are working with the Bovine Molecular Immunology Group at IAH and Stanford University to determine a complete KIR haplotype from a British Friesian. This sequence is being used as a tool to interrogate other individual British Friesians and cattle of different breeds. This comparative analysis is revealing the extent of KIR diversity in commercially important breeds and will enable the development of SNP tests for selective breeding and disease association studies.
The function of cattle KIR
To determine the functional significance of KIR gene variation it is essential to characterise gene expression ligand interactions. Working with the Bovine Molecular Immunology Group we are assessing the cell surface expression of KIR and other NK cell receptors on NK cells under a variety of stimuli. In addition, we are pairing KIR with their natural MHC class I ligands. MHC class I is also an extremely variable immune gene family located on an entirely different chromosome to the LRC genes. In combination with our work on KIR gene polymorphism, we are revealing how diversity of KIR and MHC directly impacts the function of NK cells.
Selected References
- Dobromylskyj, M., T. Connelley, J. Hammond and S. Ellis
(2009)
Cattle Ly49 is polymorphic.
Immunogenetics 61(11): 789-795. [Abstract].
- Graef, T., A. K. Moesta, P. J. Norman, L. Abi-Rached, L. Vago, A. M. Older Aguilar, M. Gleimer, J. A. Hammond, L. A. Guethlein, D. A. Bushnell, P. J. Robinson and P. Parham
(2009)
KIR2DS4 is a product of gene conversion with KIR3DL2 that introduced specificity for HLA-A*11 while diminishing avidity for HLA-C.
Journal of Experimental Medicine 206(11): 2557-2572. [Abstract].
- Goldstein T, Mazet JAK, Gill VA, Doroff AM, Burek KA, Nayden DK & Hammond JA.
(2009)
Phocine distemper virus in northern sea otters in the pacific Ocean, Alaska, USA.
Emerging Infectious Disease 15(6): 925-7. [Abstract].
- Norman PJ, Abi-Rached L, Gendzekhadze K, Hammond JA, et al.
(2009)
Meiotic recombination generates rich diversity in NK cell receptor genes, alleles and haplotypes.
Genome Research 19(5):757-69. [Abstract].
- Hammond JA, Guethlein, L, Abi-Rached, L & Parham, P.
(2009)
Evolution and survival of marine carnivores did not require a diversity of KIR or Ly49 NK cell receptors.
Journal of Immunology 182(6): 3618-27. [Abstract].
- Guethlein LA, Abi-Rached L, Hammond JA, and Parham P.
(2007)
The expanded cattle KIR genes are orthologous to the conserved single-copy KIR3DX1 gene of primates.
Immunogenetics 59(6):517-522. [Abstract].