Regulation of MHC class I and class II and their ligands in transplantation
MHC genes and molecules
We study the human major histocompatibility complex (MHC) and related loci. This key cluster of genes encodes the most polymorphic proteins in the human genome. MHC class I and class II play a pivotal role in alerting the rest of the immune system to disease. The MHC is associated with more diseases than any other region of the genome, including most autoimmune conditions, infections, cancers, drug-sensitivity and, interestingly, Parkinson's disease and schizophrenia.
Like some MHC genes, the NK receptors are part of extensive gene families. They are involved in activating, or inhibiting NK cells and some T cells. We are studying the organisation of the NK-receptor gene families, particularly KIR, their polymorphism and association with disease.
The aim is to understand the genetic and functional consequences of interactions of the receptors with different MHC class I molecules. We are investigating the roles of MHC molecules and their ligands in transplantation and ways in which they may be manipulated to promote transplantation tolerance on tissue or stem cells whilst at the same time initiating anti-leukaemia effects. To facilitate
this we have developed a novel high-throughput KIR typing system. We are in discussion with Craig Taylor regarding marketing KIR typing as a national service.
Regulation of MHC class II
Recently, mechanisms have been uncovered for post-translational regulation of MHC class II expression. We have shown that the HLA-DRA chain, as well as the DRB, chain is modified by polyubiquitination. Several viruses are known to modulate MHC class I levels by influencing their ubiquitination. We showed for the first time that Salmonella specifically down-modulates MHC class II at the cell surface by ubiquitination. These bacteria also manipulate natural killer cell responses in order to avoid immune recognition. As dendritic cells mature into professional antigen presenting cells surface MHC class II expression is increased by down-regulating ubiquitination. Several pathogens regulate MHC antigen presentation through enhancing ubiquitination of both class I and class II molecules. Understanding the mechanisms controlling surface class II expression may provide novel targets for small molecules capable of controlling surface MHC expression. Therapeutic control of MHC class II ubiquitination may restrict the initiation of adaptive immune responses in transplanted tissues and stem cells.
Sub-theme leads: John Trowsdale and Craig Taylor