T cells are white blood cells that initiate immune responses that can clear infections and cancers. The decision to respond is made by the integration of signals from a large number of different T cell surface receptors using many intracellular signalling molecules. We use a diverse set of quantitative methods to uncover the mechanisms underlying signal integration and exploit this new information to improve human health.
Quick links
Schematic of signalling proximal to the T cell antigen receptor.
T cells (red) interacting with antigen presenting cells (green).
The main focus of our research has been to understand how the immune system discriminates between normal and abnormal (e.g. infected) tissues. This job has been delegated to specialised white blood cells called T-cells. These cells patrol the body continuously scanning the surfaces of other cells for protein fragments called antigens. When their T cell antigen receptors (TCRs) bind to even a single foreign-derived antigen (e.g. a fragment from a virus) they initiate immune responses. Their TCR can also bind to highly abundant self-derived antigens (e.g. fragments of our normal proteins) with slightly lower affinity. How do T cells avoid activation when their TCR bind abundant self-antigens, yet respond when they bind even a single foreign-antigen? This is the foundational question underlying our research.
The decision to respond is made by the complicated signalling machinery that integrates signals from the TCR and a host of other, accessory, receptors on the T cell surface.
We use a combination of quantitative experiments and mathematical modelling to uncover the operational and molecular mechanisms underlying signal integration by T cell surface receptors.
A subset of the general paradigms that we work on:
-How T cells discriminate self vs. non-self foreign or neoantigen pMHC (e.g. here).
-How T cells achieve high antigen sensitivity able to respond to even a single pMHC (e.g. here).
-How T cells integrate signals from a host of accessory receptors (e.g. here).
-How T cell activation is achieved by synthetic antigen receptors (e.g. here).
-How the molecular reach of T cell surface receptors and their enzymes impact signalling (e.g. here).
-How T cells implement kinetic proofreading at a molecular level (e.g. here)
In collaboration with Oxford Biomedica, the Dushek & van der Merwe lab’s are offering a BBSRC funded DPhil studentship entitled ‘Development of Lentiviral Vectors to Induce Transient Cell Activation and Proliferation of Naïve T Cells’. Read more about the project and how to apply. Application Deadline: Friday 1st December 2023 (12:00 midday GMT).Project Start Date: 13th October 2024.
2023
Inefficient exploitation of accessory receptors reduces the sensitivity of chimeric antigen receptors.
Burton,J., Siller-Farfan, J.A., Pettmann, J., Salzer, B., Kutuzov, M., van der Merwe, P.A. and Dushek, O.
Proc Natl Acad Sci USA. – 20(2): e2216352120.
2022
Mechanical forces impair antigen discrimination by reducing differences in T cell receptor off-rates.
Pettmann, J., Awada, L., Bartosz, R., Huhn, A., Faour, S., Kutuzov, M., Limozin, L., Weikl, T.R., van der Merwe, P.A., Robert, P. and Dushek, O.
EMBO J. – 42(7): e111841.
2021
The discriminatory power of the T cell receptor.
*Pettmann, J., *Huhn, A., *Abu Shah, E., Kutuzov, M.A., Wilson, D.B., Dustin, M.L., Davis, S.J., van der Merwe, P.A. and Dushek, O.
eLife – 10: e67092.
2014
Phenotypic models of T cell activation.
Lever, M., Maini, P.K., van der Merwe, P.A. and Dushek, O.
Nature Reviews Immunology – 14(9): 619-29.
2012
Non-catalytic tyrosine-phosphorylated receptors.
Dushek, O., Goyette, J. and van der Merwe, P.A.
Immunological Reviews – 250(1): 258-76.
Improving the sensitivity of therapeutic receptors for cancer therapy
January 2023
Published in PNAS, a new paper by the Dushek group shows how the effectiveness of therapeutic chimeric antigen receptors might be improved for cancer treatment
Three Dunn School academics recognised with Full Professor title
December 2021
Many congratulations to Omer Dushek, Fumiko Esashi and Ulrike Gruneberg We are delighted to announce that three Dunn School group leaders were recognised in this year’s University of Oxford Recognition of Distinction exercise. Omer Dushek is now Professor of Molecular Immunology. His group investigates the immunology of T cell receptor signal integration, at the interface...