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Research

The laboratory is focused on understanding the 'calculation' that T cells make in deciding to respond to abnormal cells whilst ignoring healthy cells. We work within the general fields of molecular biology, systems biology, and biophysics. Below is a broad summary of our work.

Background

T cells are important white blood cells that continually circulate in the body in search of the molecular signatures ('antigens') of infection and cancer. When encountering such antigens T cells become activated and subsequently initiate immune responses in order to clear these threats. Their inappropriate activation towards innocuous and endogenous antigens leads to allergic and autoimmune responses, respectively. A key aim of the laboratory is to understand the 'calculation' that T cells make in deciding to respond to abnormal cells whilst ignoring healthy cells.

 

 

The calculation that T cells make is performed by their complex signalling machinery that integrates signals from the T cell receptor with a host of other, accessory, receptors on their surface.

 

 

Our work

We are using a combination of quantitative experiments and mathematical modelling to uncover the biochemical mechanisms used by T cells to integrate signals from their surface receptors. We use the models that we formulate to make predictions, which we experimentally test. Our ultimate goal is to use these models to understand existing therapeutics and to design new ones.

A subset of the general paradigms that we work on:

-How T cells discriminate endogenous (self) pMHC from foreign (non-self) pMHC.
-How T cells integrate signals from a host of accessory receptors.
-How the phosphorylation of T cell surface receptors is regulated.
-How tethering of signalling proteins to surface receptors impacts their activity.
-How specificity is achieved in signaling networks.
-How protein mechanics couple to protein biochemistry.

We employ a variety of quantitative experimental tools, which include biophysical methods to study protein-protein interactions (e.g. SPR) and high throughput cellular assays to systematically study T cell responses (e.g. flow cytometry, quantitative ELISAs). We routinely analyse our experimental data using mathematical modelling. The group has diverse expertise in experimental and mathematical methods.

Keywords: immunology, leukocytes, lymphocytes, T cells, immune receptors, T cell antigen receptor, signal transduction, signalling networks, network motifs, systems biology, computational biology, mathematical models, biophysics, protein-protein interactions, post-translational modifications, specificity.