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Fluctuations in T cell receptor and pMHC interactions regulate T cell activation

Fluctuations in T cell receptor and pMHC interactions regulate T cell activation
Fluctuations in T cell receptor and pMHC interactions regulate T cell activation

Adaptive immune responses depend on interactions between T cell receptors (TCRs) and peptide major histocompatibility complex (pMHC) ligands located on the surface of T cells and antigen presenting cells (APCs), respectively. As TCRs and pMHCs are often only present at low copy numbers their interactions are inherently stochastic, yet the role of stochastic fluctuations on T cell function is unclear. Here, we introduce a minimal stochastic model of T cell activation that accounts for serial TCR-pMHC engagement, reversible TCR conformational change and TCR aggregation. Analysis of this model indicates that it is not the strength of binding between the T cell and the APC cell per se that elicits an immune response, but rather the information imparted to the T cell from the encounter, as assessed by the entropy rate of the TCR-pMHC binding dynamics. This view provides an information-theoretic interpretation of T cell activation that explains a range of experimental observations. Based on this analysis, we propose that effective T cell therapeutics may be enhanced by optimizing the inherent stochasticity of TCR-pMHC binding dynamics.

immunology, information theory, mathematical model, stochastic processes, T cell activation
1742-5689
Egan, Joseph R.
cdfc53e0-3432-47bc-a148-16ed9be2262b
Abu-Shah, Enas
156515f5-6515-466c-bf92-6893c3516ba8
Dushek, Omer
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Elliott, Tim
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MacArthur, Ben D.
2c0476e7-5d3e-4064-81bb-104e8e88bb6b
Egan, Joseph R.
cdfc53e0-3432-47bc-a148-16ed9be2262b
Abu-Shah, Enas
156515f5-6515-466c-bf92-6893c3516ba8
Dushek, Omer
8f63868e-647b-400d-93a8-ddf929433cdb
Elliott, Tim
16670fa8-c2f9-477a-91df-7c9e5b453e0e
MacArthur, Ben D.
2c0476e7-5d3e-4064-81bb-104e8e88bb6b

Egan, Joseph R., Abu-Shah, Enas, Dushek, Omer, Elliott, Tim and MacArthur, Ben D. (2022) Fluctuations in T cell receptor and pMHC interactions regulate T cell activation. Journal of the Royal Society Interface, 19 (187), [20210589]. (doi:10.1098/rsif.2021.0589).

Record type: Article

Abstract

Adaptive immune responses depend on interactions between T cell receptors (TCRs) and peptide major histocompatibility complex (pMHC) ligands located on the surface of T cells and antigen presenting cells (APCs), respectively. As TCRs and pMHCs are often only present at low copy numbers their interactions are inherently stochastic, yet the role of stochastic fluctuations on T cell function is unclear. Here, we introduce a minimal stochastic model of T cell activation that accounts for serial TCR-pMHC engagement, reversible TCR conformational change and TCR aggregation. Analysis of this model indicates that it is not the strength of binding between the T cell and the APC cell per se that elicits an immune response, but rather the information imparted to the T cell from the encounter, as assessed by the entropy rate of the TCR-pMHC binding dynamics. This view provides an information-theoretic interpretation of T cell activation that explains a range of experimental observations. Based on this analysis, we propose that effective T cell therapeutics may be enhanced by optimizing the inherent stochasticity of TCR-pMHC binding dynamics.

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Accepted/In Press date: 7 December 2021
Published date: 9 February 2022
Additional Information: Funding Information: This work was funded by a PhD studentship from the School of Mathematical Sciences and the Institute for Life Sciences, University of Southampton, and an Early Career Fellowship grant from the London Mathematical Society to J.R.E., a UCB-Oxford Post-doctoral Fellowship to E.A.-S. and a Wellcome Trust Senior Fellowship in Basic Biomedical Sciences (207537/Z/17/Z 826) to O.D. Acknowledgements
Keywords: immunology, information theory, mathematical model, stochastic processes, T cell activation

Identifiers

Local EPrints ID: 470260
URI: http://eprints.soton.ac.uk/id/eprint/470260
ISSN: 1742-5689
PURE UUID: b3e08126-f873-4309-9bf5-671132f7b02a
ORCID for Joseph R. Egan: ORCID iD orcid.org/0000-0002-6414-1334
ORCID for Tim Elliott: ORCID iD orcid.org/0000-0003-1097-0222

Catalogue record

Date deposited: 05 Oct 2022 16:36
Last modified: 19 Oct 2022 01:37

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Contributors

Author: Joseph R. Egan ORCID iD
Author: Enas Abu-Shah
Author: Omer Dushek
Author: Tim Elliott ORCID iD

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