Research
Genetic and Functional Relationships between Immune Receptors
We focus on the human Major Histocompatibility Complex (MHC). This dense cluster of polymorphic loci influences susceptibility to a huge number of human diseases, including most autoimmune conditions, infections, and diverse conditions, from Narcolepsy to Schizophrenia. We investigate genetic and functional interactions between MHC products, including HFE, TRIM, BTN and MOG, in relation to disease,
The key products of the MHC are Class I and Class II. These play a pivotal role in alerting the immune system to infection by presentation of antigenic peptides to receptors on T cells. A major part of our approach concerns the regulation and functions of these molecules.
Our early work involved discovery of antigen processing molecules encoded in the MHC, such as the TAP peptide transporter and immunoproteasome subunits (J. Immunol. 2008. Pillars of Immunology: antigen presentation: discovery of the peptide TAP). Following on from this, we found a novel molecule, TAPBPR, which is related to the MHC-encoded TAPASIN molecule. TAPBPR appears to modulate MHC class I expression and may have a profound affect on immune recognition. Louise Boyle (Wellcome Career development Fellow) is leading a project to elucidate the function of TAPBPR in order to understand the role of this new player in MHC class I processing and presentation.
Further information on the state of health of a cell is provided by interaction of MHC class I molecules with other receptors on Natural Killer (NK) cells. Like some MHC genes, NK receptors form an extensive, polymorphic gene family. We are particularly interested in understanding the interplay between NK receptors and MHC class I molecules.
Publications
- Traherne JA, Martin M, Ward R, Ohashi M, Pellett F, Gladman D, Middleton D, Carrington M, Trowsdale J. (2009) Mechanisms of copy number variation and hybrid gene formation in the KIR immune gene complex.
Hum Mol Genet. In press - Lapaque N, Hutchinson JL, Jones DC, Méresse S, Holden DW, Trowsdale J, Kelly AP. Salmonella regulates polyubiquitination and surface expression of MHC class II antigens. (2009) Proc Natl Acad Sci U S A. 106:14052-7
- van Bergen J, Thompson A, Retière C, Trowsdale J, Koning F. (2009) Cutting edge: killer Ig-like receptors mediate "missing self" recognition in vivo. J Immunol. 182:2569-72.
- Young NT, Waller EC, Patel R, Roghanian A, Austyn JM, Trowsdale J. (2008) The inhibitory receptor LILRB1 modulates the differentiation and regulatory potential of human dendritic cells. Blood111, 3090-6.
- Ashiru O, Bennett NJ, Boyle LH, Thomas M, Trowsdale J, Wills MR. (2009) NKG2D ligand MICA is retained in the Golgi by the human Cytomegalovirus protein UL142. J Virol. 83, 12345-54.
Eagle RA, Traherne JA, Hair JR, Jafferji I, Trowsdale J. (2009) ULBP6/RAET1L is an additional human NKG2D ligand. Eur J Immunol. 39:3207-3216. - Lapaque N, Walzer T, Méresse S, Vivier E, Trowsdale J. (2009) Interactions between human NK cells and macrophages in response to Salmonella infection.
J Immunol. 182:4339-48. - Lapaque N, Jahnke M, Trowsdale J, Kelly AP. (2009) The HLA-DRalpha chain is modified by polyubiquitination. J Biol Chem. 284:7007-16
- Barrow AD, Trowsdale J. (2008) The extended human leukocyte receptor complex: diverse ways of modulating immune responses.
Immunol Rev. 224:98-123. - Horton R et al. (2008) Variation analysis and gene annotation of eight MHC haplotypes: the MHC Haplotype Project. Immunogenetics. 60:1-1.
- James LC, Keeble AH, Khan Z, Rhodes DA, Trowsdale J. (2007) Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function.
Proc Natl Acad Sci U S A.104:6200-5.