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Studying how lymphocytes decide to mount immune responses against, for example, tumours (cancer immunotherapy).

Davis group t cell biology 1

 

About the Research

Rather than taking clinical observations and working back to molecular causes and possible therapeutic solutions, we address important questions in human health by striving to understand the normal functioning of biological systems known to impact on disease processes. Instead of “translational medicine”, therefore, our goal is to do “translatable biology”. Specifically, we are committed to understanding, at a very basic level, the most important processes at the heart of human immune responses.

Key to all our thinking is the ‘kinetic-segregation’ (KS) model of immune receptor triggering, proposed in 1996 with Anton van der Merwe (see http://davislab-oxford.org/our-research/ks-model). The potential of our approach, we think, is well illustrated by our work on superagonistic antibodies. It is well known that certain types of tyrosine-phosphorylated receptors, which include the TCR itself, have disproportionately large impacts on immune cell function. It is also known that antibodies directed at these receptors can have extremely potent effects in humans, as revealed by the unfortunate outcome of a clinical trial of an antibody superagonist at Northwick Park in 2006. The questions are: why do these antibodies have such large effects in healthy immune systems and could we use an understanding of the mechanism as the basis of new therapeutics? Our structure of the complex of a superagonistic antibody with its cellular target, CD28, immediately suggested a general mechanism for antibody superagonism and implied that such antibodies could, in principle, be generated against a large number of receptors dependent on extrinsic tyrosine kinases (see http://davislab-oxford.org/our-research/antibodies).

By targeting inhibitory rather than activating receptors, i.e. the immune checkpoints, we expected to be able to produce intrinsically safer superagonists. We have now succeeded in generating inhibitory antibody agonists, and these are showing efficacy in in vivo models of human diseases. In the course of making the agonists, we also succeeded in generating blocking antibodies against these new targets, which could conceivably be used in new combinations with existing immune checkpoint-based immunotherapies since they show efficacy, once again, in in vivo models of cancer, working with Enzo Cerundolo and Richard Cornall. 

However, the main focus of our laboratory is the KS model. This embodies the idea that receptor, e.g. TCR signalling might only depend on receptor ‘dwell-time’ at phosphatase-depleted regions of close contact between T cells and antigen presenting cells. This model proposes that, at such contacts, the TCR remains accessible to kinases but is protected from phosphatases that would otherwise reverse its phosphorylation, resulting in the phosphorylated state being sufficiently long-lived for downstream signaling to be initiated. In this context, cognate pMHC ligands promote signaling simply by increasing the dwell time of TCRs inside the close contacts. We are seeking to show that the KS model does indeed explain receptor signaling. This work, which is fundamentally basic and molecular in nature, relies heavily on advanced fluorescence imaging methods, e.g. 3D super-resolution and light-sheet imaging, combined with quantitative approaches i.e. computer simulation and iterative model evaluation, in collaboration with David Klenerman (Cambridge University).

 

Training Opportunities

The sorts of techniques we use are tissue culture, molecular biology including genome editing, protein expression and purification, surface plasmon resonance-based binding assays, and fluorescence imaging. We put a major emphasis on thinking critically

 

Students will be enrolled on the MRC WIMM 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.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

All MRC WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the MRC WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework. The RDM also holds an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

 

Publications

Davis SJ, van der Merwe PA (2006) The kinetic-segregation model: TCR triggering and beyond. Nat Immunol. 7, 803-809.

Evans EJ, Esnouf RM, Manso-Sancho R, Gilbert RJ, James JR, Yu C, Fennelly JA, Vowles C, Hanke T, Walse B, Hunig T, Sorensen P, Stuart DI, Davis SJ.    (2005) Crystal structure of a soluble CD28-Fab complex. Nat Immunol.  6, 271-9.

Santos AM, Ponjavic A, Fritzsche M, Fernandes RA, de la Serna JB, Wilcock MJ, Schneider F, Urbančič I, McColl J, Anzilotti C, Ganzinger KA, Aßmann M, Depoil D, Cornall RJ, Dustin ML, Klenerman D, Davis SJ, Eggeling C, Lee SF. (2018) Capturing resting T cells: the perils of PLL. Nat Immunol. 19, 203-205.

Brameshuber M, Kellner F, Rossboth BK, Ta H, Alge K, Sevcsik E, Göhring J, Axmann M, Baumgart, F, Gascoigne NRJ, Davis SJ, Stockinger H, Schütz GJ,  Huppa JB (2018) Monomeric TCRs drive T-cell antigen recognition. Nat Immunol. 19, 487-496.

Paluch C, Santos AM, Anzilotti C, Cornall RJ, Davis SJ. (2018) Immune checkpoints as therapeutic targets in autoimmunity. Front Immunol In press.

Pettmann J, Santos AM, Dushek O, Davis SJ. (2018) Membrane ultrastructure and T cell activation. Front Immunol In press.


Supervisors