MHC diversity in commercial cattle herds

The main function of MHC molecules is to bind and present small fragments (peptides) derived from pathogens to immune system cells to initiate a protective response. Variation in the MHC molecules increases the range of peptides that can be recognised, thus the extreme variability of MHC genes is the key to their function; populations with high MHC polymorphism are most able to deal with rapidly evolving or new pathogens. Our preliminary data suggest that MHC diversity may be low in commercial dairy cattle populations. An increased rate of inbreeding is a consequence of livestock breeding programmes aimed at improving economically important traits. The MHC is one of the most variable regions of the genome and thus is useful for assessing loss of diversity. We have developed a system for rapid MHC typing utilising SNPs (single nucleotide polymorphisms) to further assess diversity at functional MHC loci. Our aim is for this test to be used in commercial cattle herds to circumvent the risk posed by existing selective breeding schemes. This work is part-funded by Merial.

Utilising the MHC to dissect immune responses

We have identified and characterised a significant number of MHC genes in cattle, and have developed an MHC-defined cattle herd. All validated cattle MHC sequences, along with additional information about haplotypes and nomenclature, are accessible in the immunopolymorphism database (IPD): www.ebi.ac.uk/ipd/mhc. To complement our genetically-defined animals we have generated a complete set of reagents to facilitate studies of T cell function, for example cloned MHC genes, stable transfected cells expressing single MHC genes, and MHC-peptide tetramers. We have recently generated the first cattle MHC crystal structure in collaboration with the University of Oxford. The structure demonstrates that cattle MHC molecules may have unusual peptide binding characteristics that may impact on immune responses to vaccination.

Exploring the interactions between MHC and NK receptors

The link between MHC and NK receptors has only become clear in the past few years; the repertoire of these genes forms an important component of the NK-mediated response to infectious pathogens and thus to disease susceptibility. NK cells express a range of different receptors, many of which recognise MHC class I molecules. Humans express two such gene families, the polymorphic killer cell immunoglobulin-like (KIR) genes, recognising classical class I molecules, and the relatively non-polymorphic NKG2/CD94 family, recognising non-classical class I molecules. Mice also express the latter, but instead of KIR have Ly49 genes. Cattle appear unique in that they have polymorphic KIR and Ly49 genes, and in addition their CD94/NKG2 genes are polymorphic. It is possible that this reflects the relatively complex cattle MHC system; this is currently under study.

References:

  • 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] . 
  • Dobromylskyj M, Ellis SA (2007) Complexity in cattle KIR genes: transcription and genome analysis. Immunogenetics 59: 463-472 [Abstract]. 
  • Birch J, Ellis SA (2007) Complexity in the cattle CD94/NKG2 gene families. Immunogenetics 59: 273-280 [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]. 
  • Kydd J, Davis-Poynter NJ, Birch J, Hannant D, Minke J, Audonnet JC, Antczak DF, Ellis SA (2006) A molecular approach to the identification of cytotoxic T-lymphocyte epitopes within equine herpesvirus 1. J Gen Virol 87:2507-2515 [Abstract]. 
  • Holmes E C, Roberts A F, Staines K A, Ellis SA (2003) Evolution of MHC class I genes in Cetartiodactyls. Immunogenetics 55:193-202 [Abstract].