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. We investigate genetic and functional interactions between MHC products and their receptors, 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 (J. Immunol. 2008. Pillars of Immunology: antigen presentation: discovery of the peptide TAP). Following on from this, we found a novel protein, TAPBPR, which is related to the MHC-encoded TAPASIN molecule. TAPBPR appears to modulate MHC class I expression and may have a profound effect on immune recognition. We collaborate with Louise Boyle (Wellcome Career Development Fellow), who is leading a project to elucidate the function of TAPBPR in order to understand the role of this new player in MHC class I antigen processing and presentation.
Information on the state of health of a cell is provided by interaction of MHC class I molecules with other receptors, such as those on Natural Killer (NK) and myelomonocytic lineages. Like some MHC genes, NK receptors form an extensive, polymorphic gene family. Using a novel typing system*, we identified extensive copy number variation in KIR as well as some LILR genes, which is related to disease susceptibility. We are particularly interested in understanding the interplay between NK receptors and MHC class I molecules. We are developing high-throughput KIR typing by imputation and droplet-PCR to investigate further the contribution of KIR to disease.
Boyle, L.H., Hermann, C., Boname, J.M., Porter, K.M., Patel, P.A., Burr, M.L., Duncan, L.M., Harbour, M.E., Rhodes, D.A., Skjødt, K., Lehner, P.J., Trowsdale, J. Tapasin-related protein TAPBPR is an additional component of the MHC class I presentation pathway. Proc. Natl Acad. Sci. USA 110, 3465–3470 (2013).
Béziat, V., Traherne, J. A., Liu, L. L., Jayaraman, J., Enqvist, M., Larsson, S., Trowsdale, J. and Malmberg, K. J. Influence of KIR gene copy number on natural killer cell education. Blood 121, 4703–4707 (2013).
Ammann, J. U., Cooke, A. and Trowsdale, J. Butyrophilin Btn2a2 inhibits TCR activation and phosphatidylinositol 3-kinase/Akt pathway signaling and induces Foxp3 expression in T lymphocytes. J. Immunol. 190, 5030–5036 (2013).
Jiang, W., Johnson, C., Jayaraman, J., Simecek, N., Noble, J., Moffatt, M.F., Cookson, W.O., Trowsdale, J. and Traherne, J.A. Copy number variation leads to considerable diversity for B but not A haplotypes of the human KIR genes encoding NK cell receptors. Genome Res. 22, 1845–1854 (2012).
Jahnke, M., Trowsdale, J. and Kelly, A. P. Ubiquitination of HLA-DM by different MARCH family E3 ligases targets different endocytic pathways. J. Biol. Chem. 287, 7256–7264 (2012).
Barrow, A.D., Raynal, N., Andersen, T.L., Slatter, D.A., Bihan, D., Pugh, N., Cella, M., Kim, T., Rho, J., Negishi-Koga, T., Delaisse, J.M., Takayanagi, H., Lorenzo, J., Colonna, M., Farndale, R.W., Choi, Y. and Trowsdale, J. OSCAR is a collagen receptor that costimulates osteoclastogenesis in DAP12-deficient humans and mice. J. Clin. Invest. 121, 3505–3516 (2011).
Jones, D. C, Kosmoliaptsis, V., Apps, R., Lapaque, N., Smith, I., Kono, A., Chang, C., Boyle, L. H., Taylor, C. J., Trowsdale, J. and Allen, R. L. HLA class I allelic sequence and conformation regulate leukocyte Ig-like receptor binding. J. Immunol. 186, 2990–2997 (2011).
McEwan, W. A., Mallery, D. L., Rhodes, D. A., Trowsdale, J. and James, L. C. Intracellular antibody-mediated immunity and the role of TRIM21. Bioessays 33, 803–809 (2011).