The IAH’s MHC-defined herd of Holstein cattle

We initiated our major histocompatibility complex (MHC) defined cattle herd approximately 15 years ago, to generate animals and reagents to support the work of several research groups in the Institute. Analysis and characterisation of MHC genes by the Bovine Molecular Immunology Group. (P.I. Shirley Ellis) enabled us to identify distinct haplotypes (sets of genes) present within the Holstein population at that time. Suitable bulls were identified and breeding and back-crossing over a number of years has led to the establishment of four ‘families’, each carrying a distinct set of genes.

At the same time we generated accompanying reagents and data, for example cloned MHC genes, stable transfected cell lines, peptide binding motifs, and MHC-peptide tetramers. In this way we have established a basis for sophisticated immunological studies in cattle that can rival equivalent mouse studies in terms of elegance and depth. Our MHC-defined animals represent a unique genetic resource at IAH that we intend to exploit to maintain our position at the forefront internationally of cattle disease research.

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The combination of our MHC-defined herd, the reagents that we have developed and the knowledge that we have generated means that we can perform experiments aimed at investigating T cell responses to both pathogens and vaccination, using groups of animals with an identical MHC background. It also allows us to compare responses between animals with distinctly different MHC background. These animals are only identical at the MHC and are otherwise genetically distinct, thus are not equivalent to inbred mouse strains. However, this provides us with an invaluable resource that is meaningful in the context of an outbred population.

We have now reached the stage where each of the groups contains MHC homozygous animals representing the four selected haplotypes (known by their serological definitions as A10, A14, A18, A31). In addition, we have homozygous bulls and stocks of semen to allow generation of calves for experimental purposes. In order to avoid a gradual loss of genetic diversity through continued use of a closed herd, we have instigated a system of genetically MHC typing animals in the main IAH herd (comprising animals bought from various sources), and in this way have identified some individuals that carry the required MHC haplotypes. When suitable female, MHC homozygous calves are born they are placed within the appropriate family in the MHC-defined herd, thus increasing genetic diversity in future calves used for experiments. This also ensures that the genetics of the MHC-defined herd is representative of a typical commercial dairy population. In order to keep the herd small, and to further increase its potential, we have recently set in place a programme of embryo transfer to generate groups of defined calves as requested by scientists both within and outside the IAH. Animals from the MHC herd are, in this case, used as egg and semen donors, and embryos are flushed out and implanted into recipient cows that carry the calves to term. Embryos may also be frozen for use at a later date.

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We have recently begun work on natural killer (NK) cells and their receptors. Their role is linked to that of MHC, and they are functionally crucial to the innate immune response. We have generated methods of genotyping animals for a diverse array of NK receptors, and have begun to analyse the breeding animals in the MHC-defined herd. This will add an extra dimension to the future use of these animals.

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Research Leaders within IAH who use the MHC-defined animals include:

Publications:

  • Guzman E, Taylor G, Charleston B, Skinner MA, Ellis SA (2007) An MHC-restricted CD8+ T cell response is induced in cattle by FMDV infection and also following vaccination with inactivated FMDV J Gen Virol [in press]. 
  • Gaddum, R. M., Cook, R. S., Furze, J. M., Ellis, S. A. and Taylor, G. (2003) Recognition of BRSV proteins by bovine CD8+ T lymphocytes. Immunology 108: 220-229 [Abstract]. 
  • Birch J, Murphy L, MacHugh ND, Ellis SA (2006) Generation and maintenance of diversity in the cattle MHC class I region. Immunogenetics 58:670-679 [Abstract. 
  • Dobromylskyj M, Ellis SA (2007) Complexity in cattle KIR genes: transcription and genome analysis. Immunogenetics 59:463-472 [Abstract].