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The work was led by our talented student Jose Cabezas Caballero (now a postdoc with Mala Maini) and huge thanks to all the co-authors and collaborators who made this work possible, and to Springer Nature Biomedical Engineering for an efficient review process.

This approach offers a universal method to generate highly selective therapeutic T cells for any TCR, potentially improving both the safety and effectiveness of adoptive immunotherapy for a wide range of targets.

Our work shows that by modulating co-signalling receptors on T cells (such as switching CD8 for CD4), we can significantly and selectively reduce lower-affinity off-target activation while keeping higher-affinity antitumor target efficacy intact.

In this study, we explore a novel strategy to enhance the safety of T cell immunotherapies. Traditional engineered T cell receptors (TCR-T) can sometimes cross-react with unintended lower-affinity targets, leading to harmful side effects.

The work was lead by Anna H. with support from many lab members, a fantastic collaboration with Audrey Gerard with support from Wellcome Trust and BBSRC. Thank you to EMBO Journal for a constructive and efficient review process.

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We suggest that T cells 'force-shield' their TCR/pMHC interactions at interfaces to faithfully measure their affinities.

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We show that despite the enormous molecular complexity at T cell interfaces (with target cells), the 3D affinity measured with purified TCR and pMHC in SPR can accurately predict the OT-I T cell response.

Murine T-cell receptor OT-I exhibits imperfect discrimination between foreign and self-antigens | The EMBO Journal

Our work accurately measuring the 3D affinity between the OT-I TCR and a large number of foreign and self antigen ligands is now published at EMBO Journal. Murine T-cell receptor OT-I exhibits imperfect discrimination between foreign and self-antigens www.embopress.org/doi/full/10....

embopress.org

imageimageThe OT-I mouse T-cell receptor (TCR) is thought to perfectly discriminate between lower-affinity self- and higher-affinity foreign antigen-MHC complexes. This study shows OT-I TCR to exhibit imperfect discrimination and to be activated ...

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The EMBO Journal @embojournal.org · 27/11/2025

Murine T-cell receptor OT-I exhibits imperfect discrimination between foreign and self-antigens Omer Dushek @tcell.bsky.social and colleagues show that 3D solution affinities of the OT-I TCR for foreign and self-antigens predict functional T-cell responses www.embopress.org/doi/full/10....

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Malcolm Sim @mjwsim.bsky.social · 23/10/2025

UK NK 2026 in Cardiff. January 9th. Be there. eventbrite.co.uk/e/uk-nk-confer… Hosted by Rich Stanton, Ceri Fielding & Eddie Wang

eventbrite.co.uk

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Matthew Freeman @mjafreeman.bsky.social · 22/09/2025

I was Chair of @biologists.bsky.social when we started this initiative, the brainwave of the @stevenkelly.bsky.social It was an imaginative idea and I am thrilled to see this landmark Remember: @biologists.bsky.social are the goodies in scientific publishing!

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Jun Allard @allardlab.bsky.social · 08/09/2025

We can make the flexibility of a model match the hypothesis being tested -- more flexibility is not always better, if it prohibits rejection of the hypothesis. Here is one simple case involving T cells where it made a difference! www.biorxiv.org/content/10.1...

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Omer Dushek @tcell.bsky.social · 04/08/2025

If you're a postdoc interested in starting your own group, please consider the Dunn School at Oxford, UK. It's a fantastic department and university for molecular immunology and all aspects of immune research!

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Immunotherapy Advances @imtadvances.bsky.social · 17/07/2025

Temporal control of cytokine production is lost in 2nd-gen CAR-T cells, says Patel et al. This could be key to understanding their efficacy and toxicity in cancer immunotherapy. 🧬 🔗 bit.ly/4lOLicw #CancerImmunotherapy

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Thanks to our funding, collaborators, constructive reviewers, and for the very efficient process at Immunology & Cell Biology!

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By comparing the advantages and limitations of each platform, we provide a framework to choose the most suitable system to study signal integration in both basic and translational contexts.

A recently developed CombiCell system enables easy manipulation of ligands while conserving key biophysical properties.

In contrast, solid surfaces or supported lipid bilayers allow easy manipulation of ligands but lack the biophysical properties of cells, such as softness, a glycocalyx, and/or ligand mobility.

Although genetically modified antigen-presenting cells (APCs) offer the most physiological system, manipulating their ligands is difficult and slow.

We review and compare the available platforms, focusing on T-cell recognition.

Since they encounter a huge variety of normal and abnormal cells, they experience many different combinations and concentrations of ligands. Understanding immune responses therefore requires platforms that enable ligands to be easily manipulated.

Immune cells interact directly with other cells and make decisions by integrating information from many different receptor–ligand interactions at these cell–cell interfaces.

Dimova Lab @dimovalab.bsky.social · 09/05/2025

Our new review article led by Jordan Kramer: Platforms for studying cell–cell recognition by immune cells onlinelibrary.wiley.com/doi/10.1111/...

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📢 Registration is open for the Biomembrane Days 2025! 🔗 biomembrane-days-2025.mpikg.mpg.de A top-notch lineup of speakers, 120 posters, 200 scientists. 📜Submit an abstract by July 14 🏆3 Poster prizes ⚠️Limited spots-previous events were fully booked! #BiomembraneDays2025 #Biophysics #CellMembranes

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Omer Dushek @tcell.bsky.social · 01/04/2025

Sofia has been exploiting the platform to study T cell signal integration by co-signalling receptor/ligand interactions.

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Omer Dushek @tcell.bsky.social · 01/04/2025

CombiCells allow combinatorial display of cell surface ligands www.nature.com/articles/s41... A new Tools of the Trade article from Nature Reviews Immunology by Sofía Bustamante Eguiguren in our lab highlights the CombiCell platform to combinatorially display and titrate many cell surface ligands

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Omer Dushek @tcell.bsky.social · 06/03/2025

The molecular reach of antibodies crucially underpins their viral neutralisation capacity Our work on measuring and understanding the role of molecular reach on antibody function is now part of a list of editor's pick manuscripts: www.nature.com/collections/...

nature.com

Microbiology and infectious diseases

This page highlights recent articles on all aspects of bacteriology, mycology, parasitology and virology, covering the biology of pathogens, host-pathogen ...

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Omer Dushek @tcell.bsky.social · 22/02/2025

A fantastic EACR conference that focuses on all aspects of immune responses to cancer! Barcelona - May 2025

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British Society for Immunology @britsocimm.bsky.social · 06/02/2025

📢 LAST CHANCE to submit your abstracts for BSI Oxford and @immunologyoxford.bsky.social's #OIS25 Symposium This is your opportunity to take part in this celebration Oxford's outstanding #immunology research 🔬 Submissions are open until midnight on Friday 7th Feb 👉 bit.ly/4elJmnG

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British Society for Immunology @britsocimm.bsky.social · 30/01/2025

📢 Abstract submission for BSI Oxford and @immunologyoxford.bsky.social 's #OIS25 Symposium closes NEXT WEEK (7 Feb) Don't miss your chance to take part in this celebration of the outstanding #immunology research happening across Oxford 💫 Submit your abstract here 👉 bit.ly/4elJmnG

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ilesla.bsky.social @ilesla.bsky.social · 16/01/2025

Two weeks to go until the application deadline for ILESLA. If you or anyone you know would benefit from full funding to carry out a PhD in Life and/or Environmental Science please visit/refer to our website page iles.web.ox.ac.uk/how-apply where you can see open day videos and get full guidance.

iles.web.ox.ac.uk

How to Apply and Funding

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The Dunn School, Oxford @dunnschool.bsky.social · 14/01/2025

We just can't stop recruiting! Associate professor in cell and molecular biology @dunnschool, with a preference for immunology, inflammation and/or infection - all defined broadly Come and be our colleague Deadline 28 Feb, please spread the word www.path.ox.ac.uk/vacancy/asso...

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Gerard Lab @gerardlab.bsky.social · 16/01/2025

The OT-I TCR is often criticised as being very high-affinity and displaying unusual behaviour compared to other TCR transgenics. New work from @tcell.bsky.social shows this might not be the case. Will I still use OT-I and all the wonderful tools associated with it? Yes I will!

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This was a fantastic effort led by Anna Huhn and a collaboration with @gerardlab.bsky.social. We thanks for our funders @wellcometrust.bsky.social Wellcome Trust and our fantastic department @dunnschool.bsky.social Dunn School

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Taken together, our 3D affinities enable us to resolve discrepancies between the OT-I and other TCRs used in the literature.

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Our results underline the ability of T cells to effectively gauge proxies for 3D affinity within the 2D cell-cell interface, which is predicted by a model whereby the TCR/pMHC interactions are shielded by molecular forces (e.g. Pettmann et al (2023) EMBO J; Schrangl et al (2024) bioRxiv)

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We find high correlations between 3D affinities and 2D affinities, and with T cell responses. We don’t find a sharp affinity threshold but rather imperfect antigen discrimination. We show that the kinetic proofreading mechanism can explain this level of discrimination with high antigen sensitivity.

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We find that the OT-I interaction with its foreign OVA antigen has physiological affinity (KD = 34 uM) with a short half-life (<1 s) and has a remarkably low affinity to positively selecting peptides (KD > 2000 uM).

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In this study, we use a new method to accurately measure 3D TCR/pMHC affinities at 37C between OT-I and 19 peptides commonly used in the literature, including positively selecting self peptides.

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This raises critical questions about the generalizability of findings derived from the widely used OT-I system and its relevance to broader T cell biology.

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Moreover, the OT-I interaction with its foreign OVA antigen was reported to have an extremely long half-life (~533 seconds at 37C) giving rise to the notion that it is an unusual TCR.

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However, this degree of peripheral discrimination has not been observed in other, less commonly used TCRs, revealing a significant discrepancy between the OT-I TCR and other models (e.g. see Pettmann et al (2021) eLife, elifesciences.org/articles/67092).

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