Multi-dimensional analysis of the immunological synapse in the context of immunotherapy

PROJECT OVERVIEW

The adaptive immune response is initiated by molecular interactions in the nanoscale gap between T lymphocyte and antigen presenting cell. If these interactions are appropriately tuned across a network of interacting physiological systems, the host is protected against a universe of external threats from pathogens and internal threats from cancer and autoimmunity. Failure to successfully coordinate these interactions can lead to pathogen or tumour escape at one extreme and autoimmune diseases at the other extreme. Microbial co-evolution shapes protection at the cost of a significant burden of autoimmunity. This equilibrium between protection and immunopathology is encoded in part in the network of cell-cell interactions and their biophysical constraints. This project focuses on a deeper understanding of core principles of cell-cell communication in the immune response.

Progress in this effort over the last 40 years has benefited greatly from model systems based on supported lipid bilayer technology that can be used to reconstitute simplified 2D immunological synapses with live immune cells using two or more molecularly defined components to provide dynamic adhesion and immunologically specific signalling. The immunological receptors can be diversified along several axes to tune up or down the strength and qualities of the response to mimic different biological contexts. This model is maintained in the lab and will be available to ask specific molecular/biophysical questions throughout the project.

The technical frontier is to obtain a similar quality of information about complex 3D cell-cell interfaces as we currently do in 2D settings. This would enable a deeper understanding the relevant biophysical parameters and regulatory potential at the interface of two live cells. Lattice light sheet microscopy is a step in this direction and we are making concerted efforts to address both the fluorescent tagging strategies and image analysis technologies needed to advance in this direction for both in vitro cell-cell interactions and in situ interactions in tissues and even in vivo using animal models.

A specific question that can be addressed in this project is to investigate mechanisms of therapeutic anti-CD3 antibodies and bispecific engagers that can be used in the context of autoimmune disease and cancer therapies. We have developed hypotheses based on supported lipid bilayer and in vitro lattice light sheet microscopy that we propose to further test using these platforms and extend into in situ imaging in tissues and experimental medicine studies.

KEYWORDS

Synapses

Signalling

Immunotherapy

Biologics

Microscopy 

TRAINING OPPORTUNITIES

This project provides a broad training in cell biology of the immune response, with comprehensive coverage of standard and advanced techniques including multiomic analysis of human cells and tissues, spectral flow cytometry, advanced microscopy (lattice light sheet, confocal, TIRF, multiphoton laser scanning, etc), biochemistry, nanotechnology, mechanobiology and proteomics. Exciting new technologies such as lattice light sheet microscopy are integral to the project with commercial (Oxford-Zeiss Centre of Excellence) and custom-built systems available (BioCOP, Rosalind Franklin Institute). This project could be offered as part of a clinical DPhil through addition of appropriate supervisors. 

KEY PUBLICATIONS

Capera J, Jainarayanan AK, Valvo S, Chen L, Quayle SN, Moniz RJ, Suri A, Dustin M. Synaptic synergy of T cell receptor and interleukin 2 receptor in CD8+ T cells. bioRxiv. 2024:2024.08.13.607831. doi: 10.1101/2024.08.13.607831.

Kondo T, Bourassa FXP, Achar S, DuSold J, Cespedes PF, Ando M, Dwivedi A, Moraly J, Chien C, Majdoul S, Kenet AL, Wahlsten M, Kvalvaag A, Jenkins E, Kim SP, Ade CM, Yu Z, Gaud G, Davila M, Love P, Yang JC, Dustin ML, Altan-Bonnet G, Francois P, Taylor N. Engineering TCR-controlled fuzzy logic into CAR T cells enhances therapeutic specificity. Cell. 2025;188(9):2372-89 e35. doi: 10.1016/j.cell.2025.03.017. PubMed PMID: 40220754.

Novak-Kotzer H, Capera J, Jainarayanan A, Elanchezhian M, Valvo S, Mayya V, Zanin-Zhorov A, Macdonald J, Taylor PC, Dustin ML. STAT3 phosphorylation in the rheumatoid arthritis immunological synapse. J Autoimmun. 2025;155:103456. doi: 10.1016/j.jaut.2025.103456. PMID: 40609233.

Lau VWC, Mead GJ, Varyova Z, Mazet JM, Krishnan A, Roberts EW, Prota G, Gileadi U, Midwood KS, Cerundolo V, Gerard A. Remodelling of the immune landscape by IFNgamma counteracts IFNgamma-dependent tumour escape in mouse tumour models. Nat Commun. 2025;16(1):2. doi: 10.1038/s41467-024-54791-0. PubMed PMID: 39746898.

Schneider F, Cespedes PF, Karedla N, Dustin ML, Fritzsche M. Quantifying biomolecular organisation in membranes with brightness-transit statistics. Nat Commun. 2024;15(1):7082. doi: 10.1038/s41467-024-51435-1. PubMed PMID: 39152104 

THEMES

Immunology

Molecular, Cell and Systems Biology

Microbiology, Infection and Tropical Medicine

Translational Medicine and Medical Technology

CONTACT INFORMATION OF ALL SUPERVISORS

michael.dustin@kennedy.ox.ac.uk

audrey.gerard@kennedy.ox.ac.uk

marco.fritzsche@kennedy.ox.ac.uk

edward.kennedy@kennedy.ox.ac.uk

panyu.fei@kennedy.ox.ac.uk

jesusa.caperaaragones@kennedy.ox.ac.uk