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Friday, January 08, 2021 Competition Funded PhD Project (Students Worldwide)

About the Project

Our focus has been on the cell biology of the T-cell surface. We developed general methods for crystallizing glycoproteins and determined the structures of key T-cell surface proteins including the first adhesion protein (CD2) and its ligand CD58, the costimulatory receptor CD28 and its ligand CD80, and the large tyrosine phosphatase CD45. We also worked out how weak, specific recognition is achieved by these types of proteins and obtained the first insights into the overall composition of the T-cell surface. Most importantly we proposed, with PA van der Merwe, one of the most complete and best-supported explanations for leukocyte receptor triggering, called the kinetic-segregation model (youtube.com/watch?v=HygSTSlycok). Please see http://davislab-oxford.org/ for more details of our lab’s activities.

A dark secret at the heart of Immunology is that we don’t properly understand how immune responses start, i.e. how the T-cell receptor (TCR) is “triggered” by binding to peptide/MHC. We proposed that TCR phosphorylation is maintained by an equilibrium between kinases and large phosphatases, such as CD45, that’s disturbed locally in favour of kinases when TCRs engage their small ligands, owing to the exclusion of the phosphatases from regions of contact. Using fluorescence and super-resolution microscopy we discovered that, during encounters of T cells with artificial and model cell membranes, sub-μm “close-contacts” do indeed form that exclude CD45 and trap smaller molecules including the TCR. What we now want to understand is what happens inside these close-contacts. And even more, what we’d like to know is what happens if/when T-cells form close-contacts with antigen-presenting cells, which is going to require very sophisticated, super-resolution fluorescence imaging. To do this we work closely with Prof David Klenerman (Cambridge University) and Dr Christoffer Lagerholm (here at the Weatherall Institute).

Alongside these basic-science experiments, we’re trying to use our insights into receptor signaling to develop new immunotherapies. Decisions leading to lymphocyte survival or death are decided not just by the TCR but also by activating or inhibitory receptors that provide positive or negative selection signals and tune cells to vital cues in their environment. Understanding these processes has led to the development of blocking antibodies and fusion proteins that prevent signalling by masking the ligands of inhibitory receptors, an approach transforming cancer immunotherapy. The opposite strategy of using agonistic antibodies to activate these inhibitory pathways in the context of, e.g., autoimmunity has not been attempted, however, despite the remarkable potency of these receptors revealed by immune checkpoint blockade. If we could create a new class of antibody superagonists capable of activating inhibitory receptors at will it would be a major therapeutic advance.

On the other hand, the single most important development in medicine in the last 10 years is the advent of immune checkpoint therapy for cancer. In the course of making antibody superagonists, we produced antibodies against four immune checkpoints, all of which we expect to block signalling. One of these receptors is PD-1; the other three are relatively new and two of them, as far as we aware, are yet to be fully explored as targets of experimental combination- or monotherapies for cancer. Our laboratory is trying to understand how these antibodies work using, e.g., whole-genome CRISPR screens and antibody engineering, and to translate these findings into second-generation cancer immunotherapies.

The work in the Davis Laboratory relies on the use of CRISPR and other molecular biology-related techniques to generate and express fluorescently tagged signaling proteins, and to study and characterize the effects of antibodies, and to re-engineer them. Training in cutting edge imaging will be obtained in the laboratories of our collaborators.

Additional supervision may be provided by Dr Mafalda Santos and Dr Sumana Sharma

Students will be enrolled on the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Additional information about training opportunities can be found on our website.

Funding Notes

Funding for this project is available to scientists through the WIMM Prize Studentship and the RDM Scholars Programme, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.

For October 2021 entry, the application deadline is 8th January 2021 at 12 noon midday, UK time.

Please visit our website for more information on how to apply.

References

Chang VT, Fernandes RA, Ganzinger KA, et al. Initiation of T cell signaling by CD45 segregation at 'close contacts'. Nat Immunol. 2016 17, 574-582.

Felce JH, Sezgin E, Wane M, et al. CD45 exclusion- and cross-linking-based receptor signaling together broaden FcεRI reactivity. Sci Signal. 2018 11, eaat0756.

Paluch C, Santos AM, Anzilotti C, Cornall RJ, Davis SJ. Immune checkpoints as therapeutic targets in autoimmunity. Front Immunol. 2018 9, 2306.

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