Mechanical force matters in T-cell activation

In the last 20 years there has been an emerging recognition that tumours modulate their mechanics to evade the human immune system (1). Cytotoxic CD8+ T cells (CTLs) have become known to adapt their ability to generate mechanical forces to modulate the process of self-nonself antigen discrimination in the tumour micro-environment. Although experiments have long indicated that tumours have different mechanical properties compared to healthy tissues, we and others have now acquired evidence that these aberrations have a profoundly negative impact on the ability of mechanoadaption and thus of self-nonself discrimination of activating CTLs in tumours.

However, the biological significance of mechanosensation for self-nonself antigen discrimination remains controversial. CTLs discriminate between self- and non-self antigens by unique T-cell receptor (TCR) - peptide major histocompatibility complex (pMHC) interactions and a number of co-receptors presented on antigen presenting cells (APCs). Recent findings suggests that mechanical force contributes to the discriminating capabilities of this interaction, providing a possible explanation for differences in T-cell responses according to the mechanical properties of APCs presenting the pMHCs. Studies to test these hypotheses remain inconclusive due to the inability to accurately measure these small mechanical  forces.

We have recently demonstrated in our theoretical analysis that T-cell self-nonself antigen discrimination depends on mechanical force (2). We found that the lifetime of TCR bonds depends on TCR rigidity, frequency of fluctuating mechanical force, as well as the T-cell and APC stiffnesses. This project addresses the scientific need to investigate how mechanical force underpin self-nonself discrimination in T-cell activation. With support of the Oxford-ZEISS Centre of Excellence at the Kennedy Institute and its flagship instrument the ZEISS Lattice Light Sheet (LLSM) we will measure three-dimensional (3D) forces between T cells and APCs. To better understand the mechanisms of mechanoadaption of CTLs, we utilise our novel workflow of synthetic APC Traction Force Microscopy (TFM) technique that allows to detect 3D forces in the pico-Newton range which is based on our previous work (3,4). Exploiting new ImmTAC (Immune mobilising monoclonal T-cell receptors Against Cancer) technology molecules as a model in collaboration with Immunocore, we will enable to study the impact of altering affinity for target and CD3 on the potency and specificity of the redirected T-cell response (5). Combining super soft polyacrylamide hydrogels with stiffnesses below 1 kPa with various antigen densities and ImmTac technoogy from Immunocore will reveal the working principles of self-nonself discrimination in activating CTL and synthetic APCs with physiological relevant conditions. This study has the potential to resolve the role of mechanical force in T-cell self-nonself discrimination with unprecedented sensitivity exploiting advanced force probing and bioimaging technologies. 

KEYWORDS

Synthetic biology, Immunological Synapse, T cells, ImmTAC technology, Traction Force Microscopy

TRAINING OPPORTUNITIES

Well-established DPhil programme with defined milestones, ample training opportunities within the university, and access to university/department-wide seminars by world leading scientists

Access and training at the Oxford-ZEISS Center of Excellence and Rosalind Franklin Institute

Novel sensitive force probing technologies such as astigmatic Traction Force Microscopy (aTFM) and 2D Total-Internal-Reflection-Fluorescence Structured-Illumination-Microscopy (2D-TIRF-SIM)

Highly collaborative environment between University of Oxford ranging from state-of-the-art molecular biology to advanced microscopy

KEY PUBLICATIONS

(1) Dieckmann NM, Frazer GL, Asano Y, Stinchcombe JC, Griffiths GM, The cytotoxic T lymphocyte immune synapse at a glance, JCS 2016.

(2) Fritzsche & Kruse, Mechanical force matters in T-cell activation, PNAS 2024.

(3) Li D, Colin-York H, Barbieri L, Javanmardi Y, Guo T, Korobchevskaya K, Moendarbary E, Li D, Fritzsche M, Astigmatic Traction force microscopy (aTFM), Nature Communications, 2021.

(4) Barbieri L, Colin-York H, Korobchevskaya K, Li D, Karedla N, Schneider F, Dustin M, Li D, Fritzsche M, Two-dimensional TIRF-SIM Traction Force Microscopy (2D TIRF-SIM-TFM), Nature Communications, 2021.

(5) Robertson IB, Mulvaney R, Dieckmann N, Vantellini A, Canestraro M, Amicarella F, O'Dwyer R, Cole DK, Harper S, Dushek O, Kirk P, Tuning the potency and selectivity of ImmTAC molecules by affinity modulation, Clinical Experimental Medicine 2024.

THEMES

Immunology, Tissue, Imaging, data

CONTACT INFORMATION OF ALL SUPERVISORS

marco.fritzsche@kennedy.ox.ac.uk

michael.dustin@kennedy.ox.ac.uk

huw.colinyork@kennedy.ox.ac.uk

anna.schepers@kennedy.ox.ac.uk

The Kennedy Institute is a proud supporter of the Academic Futures scholarship programme, designed to address under-representation and help improve equality, diversity and inclusion in our graduate student body.  The Kennedy and the wider University rely on bringing the very best minds from across the world together, whatever their race, gender, religion or background to create new ideas, insights and innovations to change the world for the better. Up to 50 full awards are available across the three programme streams, and you can find further information on each stream on their individual tabs (Academic futures | Graduate access | University of Oxford).

How to Apply

Please contact the relevant supervisor(s), to register your interest in the project, and the departmental Education Team (graduate.studies@ndorms.ox.ac.uk), who will be able to advise you of the essential requirements for the programme and provide further information on how to make an official application.

Interested applicants should have, or expect to obtain, a first or upper second-class BSc degree or equivalent in a relevant subject and will also need to provide evidence of English language competence (where applicable). The application guide and form is found online and the DPhil or MSc by research will commence in October 2025. 

Applications should be made to the following programme using the specified course code.

D.Phil in Molecular and Cellular Medicine (course code: RD_MP1)

For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford.

Interviews to be held week commencing 13^th January 2025.