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Mechanical forces impair antigen discrimination by reducing differences in T cell receptor off-rates

View ORCID ProfileJohannes Pettmann, View ORCID ProfileLama Awada, View ORCID ProfileBartosz Różycki, View ORCID ProfileAnna Huhn, Sara Faour, View ORCID ProfileMikhail Kutuzov, View ORCID ProfileLaurent Limozin, View ORCID ProfileThomas R. Weikl, View ORCID ProfileP. Anton van der Merwe, View ORCID ProfilePhilippe Robert, View ORCID ProfileOmer Dushek
doi: https://doi.org/10.1101/2022.05.05.490751
Johannes Pettmann
1Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE, Oxford, UK
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  • ORCID record for Johannes Pettmann
Lama Awada
2Laboratoire Adhesion et Inflammation, Aix Marseille University UM 61, INSERM UMRS 1067, CNRS UMR 7333, Marseille F-13288, France
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Bartosz Różycki
3Institute of Physics, Polish Academy of Sciences, Al. Lotników 32/46, 02-668 Warsaw, Poland
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Anna Huhn
1Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE, Oxford, UK
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Sara Faour
2Laboratoire Adhesion et Inflammation, Aix Marseille University UM 61, INSERM UMRS 1067, CNRS UMR 7333, Marseille F-13288, France
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Mikhail Kutuzov
1Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE, Oxford, UK
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Laurent Limozin
2Laboratoire Adhesion et Inflammation, Aix Marseille University UM 61, INSERM UMRS 1067, CNRS UMR 7333, Marseille F-13288, France
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Thomas R. Weikl
4Max Planck Institute of Colloids and Interfaces, Potsdam, Germany
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P. Anton van der Merwe
1Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE, Oxford, UK
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  • For correspondence: anton.vandermerwe@path.ox.ac.uk philippe.robert@inserm.fr omer.dushek@path.ox.ac.uk
Philippe Robert
2Laboratoire Adhesion et Inflammation, Aix Marseille University UM 61, INSERM UMRS 1067, CNRS UMR 7333, Marseille F-13288, France
5Assistance Publique-Hôpitaux de Marseille, Marseille France
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  • For correspondence: anton.vandermerwe@path.ox.ac.uk philippe.robert@inserm.fr omer.dushek@path.ox.ac.uk
Omer Dushek
1Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE, Oxford, UK
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  • For correspondence: anton.vandermerwe@path.ox.ac.uk philippe.robert@inserm.fr omer.dushek@path.ox.ac.uk
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Abstract

T cells use their T cell receptors (TCRs) to discriminate between lower-affinity self and higher-affinity foreign peptide major-histocompatibility-complexes (pMHCs) based on the TCR/pMHC off-rate. It is now appreciated that T cells generate mechanical forces during this process but how force impacts the TCR/pMHC off-rate remains unclear. Here, we measured the effect of mechanical force on the off-rate of multiple TCR/pMHC interactions. Unexpectedly, we found that lower-affinity pMHCs with faster solution off-rates were more resistant to mechanical force (weak slip or catch bonds) than higher-affinity interactions (strong slip bonds), and this was confirmed by molecular dynamic simulations. Consistent with these findings, we show that the best characterized catch-bond, involving the OT-I TCR, has a low affinity and an exceptionally fast solution off-rate. Our findings imply that reducing forces on the TCR/pMHC interaction improves antigen discrimination and we suggest this new force-shielding role for the adhesion receptors CD2 and LFA-1.

One sentence summary Mechanical forces disproportionately accelerate the off-rates of higher-affinity antigens reducing T cell antigen discrimination

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted May 05, 2022.
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Mechanical forces impair antigen discrimination by reducing differences in T cell receptor off-rates
Johannes Pettmann, Lama Awada, Bartosz Różycki, Anna Huhn, Sara Faour, Mikhail Kutuzov, Laurent Limozin, Thomas R. Weikl, P. Anton van der Merwe, Philippe Robert, Omer Dushek
bioRxiv 2022.05.05.490751; doi: https://doi.org/10.1101/2022.05.05.490751
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Mechanical forces impair antigen discrimination by reducing differences in T cell receptor off-rates
Johannes Pettmann, Lama Awada, Bartosz Różycki, Anna Huhn, Sara Faour, Mikhail Kutuzov, Laurent Limozin, Thomas R. Weikl, P. Anton van der Merwe, Philippe Robert, Omer Dushek
bioRxiv 2022.05.05.490751; doi: https://doi.org/10.1101/2022.05.05.490751

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