Cambridge Institute for Medical Research

Professor John Trowsdale

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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, 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.

In addition, our pioneering work on a novel IgG-binding molecule, TRIM21 (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 104:6200-5) underpins current understanding of this molecule as an intracellular Immunoglobulin receptor as part of the innate immune system.

Funding

• Wellcome Trust (Programme grant)
• MRC (Programme grant)

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