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Professor John Trowsdale

Professor John Trowsdale

John Trowsdale is accepting applications for PhD students.

John Trowsdale is available for consultancy.


Research Interests

The human major histocompatibility complex (MHC) encodes the most polymorphic proteins in the human genome and is associated with more diseases than any other region. Unravelling this complex of human loci, from sequence to function, will help to understand autoimmune diseases such as diabetes, multiple sclerosis and arthritis. The class I and class II molecules encoded by the MHC play a pivotal role in alerting the rest of the immune system to disease by interacting with receptors on T cells. A major part of our work concerns these molecules. Other genes embedded in the MHC provide additional clues to mechanisms of immune recognition and we are studying the functions of some of them, including TRIM, BTN. Both of these sets of molecules contain a B30.2 (PRYSPRY) domain. In the course of studying the function of this domain we found that TRIM21 is an intracellular antibody receptor (Rhodes and Trowsdale J. Mol Immunol. 2007 44:2406). 

Further information on the state of health of a cell is provided by interaction of MHC class I molecules with receptors, other than T cell receptors, on natural killer (NK) cells, macrophages and dendritic cells. 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. Similarly, the related LILR molecules are involved in controlling cells of the myeloid lineage. We are studying the organisation of the NK-receptor gene families, their polymorphism and association with disease, particularly in relation to interaction of the receptors with different MHC class I molecules.

 

Keywords

NK ; MHC class I ; KIR ; processing ; MHC ; presentation

Key Publications

Bashirova AA, Martin-Gayo E, Jones DC, Qi Y, Apps R, Gao X, Burke PS, Taylor CJ, Rogich J, Wolinsky S, Bream JH, Duggal P, Hussain S, Martinson J, Weintrob A, Kirk GD, Fellay J, Buchbinder SP, Goedert JJ, Deeks SG, Pereyra F, Trowsdale J, Lichterfeld M, Telenti A, Walker BD, Allen RL, Carrington M, Yu XG. (2014) LILRB2 interaction with HLA class I correlates with control of HIV-1 infection. PLoS Genet.  10(3):e1004196.

López-Álvarez MR, Jones DC, Jiang W, Traherne JA, Trowsdale J. (2014) Copy number and nucleotide variation of the LILR family of myelomonocytic cell activating and inhibitory receptors. Immunogenetics. 66(2):73-83.

Trowsdale J, Knight JC. (2013) Major histocompatibility complex genomics and human disease. Annu Rev Genomics Hum Genet. 14:301-23. 

Ammann JU, Cooke A, Trowsdale J. (2013) Butyrophilin Btn2a2 inhibits TCR activation and phosphatidylinositol 3-kinase/Akt pathway signaling and induces Foxp3 expression in T lymphocytes. J Immunol. 190(10):5030-6. 

Boyle LH, Hermann C, Boname JM, Porter KM, Patel PA, Burr ML, Duncan LM, Harbour ME, Rhodes DA, Skjødt K, Lehner PJ, Trowsdale J. (2013) Tapasin-related protein TAPBPR is an additional component of the MHC class I presentation pathway.
Proc Natl Acad Sci U S A.110(9):3465-70.

Jiang W, Johnson C, Jayaraman J, Simecek N, Noble J, Moffatt MF, Cookson WO, Trowsdale J, Traherne JA. (2012) Copy number variation leads to considerable diversity for B but not A haplotypes of the human KIR genes encoding NK cell receptors. Genome Res. 22:1845-54.

Barrow AD, Raynal N, Andersen TL, Slatter DA, Bihan D, Pugh N, Cella M, Kim T, Rho J, Negishi-Koga T, Delaisse JM, Takayanagi H, Lorenzo J, Colonna M, Farndale RW, Choi Y, Trowsdale J. (2011) OSCAR is a collagen receptor that costimulates osteoclastogenesis in DAP12-deficient humans and mice. J Clin Invest. 121:3505-16.

Rhodes DA, Boyle LH, Boname JM, Lehner PJ, Trowsdale (2010) Ubiquitination of lysine-331 by Kaposi's sarcoma-associated herpesvirus protein K5 targets HFE for lysosomal degradation.  Proc Natl Acad Sci U S A. 107:16240-5.

Traherne JA, Martin M, Ward R, Ohashi M, Pellett F, Gladman D, Middleton D, Carrington M, Trowsdale J. (2010) Mechanisms of copy number variation and hybrid gene formation in the KIR immune gene complex. Hum Mol Genet. 19:737-51.

Trowsdale J, Hanson I, Mockridge I, Beck S, Townsend A, Kelly A. (2008) ‘Pillars of Immunology’: Sequences encoded in the class II region of the MHC related to the 'ABC' superfamily of transporters. 1990. J Immunol. 180:2733-6.

Young NT, Waller EC, Patel R, Roghanian A, Austyn JM, Trowsdale J. The inhibitory receptor LILRB1 modulates the differentiation and regulatory potential of human dendritic cells. Blood. 2008 111:3090-6.

Using a novel, high-throughput copy number assay for KIR typing we have shown that there are many unconventional arrangements of KIR genes. This assay can be used to understand the relationship between MHC class I molecules, their receptors and disease conditions, including autoimmunity, infection, matching in stem cell transplants for leukaemia and disorders of pregnancy (see reference by Jiang et al. 2012).