Tim Elliot - Overview

Cytotoxic T cells (CTL) are an important arm of our immune defence against the development of tumours. CTL recognise fragments of protein antigens (epitopes), derived from tumours, bound to polymorphic receptor molecules encoded by the Major Histocompatibility Complex (class I) on the surface of tumour cells.

The process of generating peptide fragments from tumour proteins is known as antigen processing, and the formation of a complex, between these peptides and MHC class I molecules, which can be seen by circulating CTL is known as antigen presentation. A major focus of our lab is point where these two processes meet. Here, polypeptide fragments containing CTL epitopes are transported from the cytosol, where they are made, into the endoplasmic reticulum (ER) where MHC class I molecules are synthesised. This requires a specialised peptide transporter - the recently discovered Transporter Associated with Antigen Processing or TAP. Once in the ER the polypeptide fragments can be trimmed to an optimal size for binding to newly synthesised MHC class I molecules. Assembly of class I molecules with antigenic peptides is tightly regulated by several cofactor molecules in the ER including tapasin, calretculin and ERp57. The complex is then transported to the cell surface where it can be recognised by T cells. We are investigating the molecular mechanisms that underpin these phenomena in normal cells and in cancer cells with a view to understanding how tumour cells can escape immune recognition, and how immunity to tumours might be improved.

We are also interested in how T cells recognise peptide antigens that carry post-translational modifications such as glycosylation or phosphorylation. Such structures might arise as a consequence of malignant transformation and so would be ideal candidates for tumour-specific antigens. So far, we have shown that T cells can specifically recognise O-linked GlcNAc residues and phosphate groups and have solved the X-ray crystal structure of an MHC class molecule bound to two glycopeptides to get a better idea of how this happens at the atomic level. Projects are underway to identify naturally presented post-translationally modified peptides from various tumours. Glycosylation of transmembrane proteins can also modulate their immunogenicity, as we have recently shown for an immunodominant murine tumour antigen. We are investigating the mechanism underpinning this phenomenon – in particular the role of lectin-like chaperone binding to potential antigens.

We are also investigating the role of regulatory T cells in inhibiting T cell responses (both CD8+ and CD4+) to tumour antigens. We have found that depleting CD4+ regulatory T cells bearing the cell-surface molecule CD25 promotes a strong protective T cell response to (normally) non-immunogenic tumours in model systems. T cell immunity is long lasting and is different to immunity that can be provoked by adjuvants in that it involves CD4+ as well as CD8+ effector cells.