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Phenotypic models of T cell activation

Nature Reviews Immunology volume 14, pages 619–629 (2014)Cite this article

Subjects

Key Points

  • Many studies have aimed to relate the binding parameters of T cell receptor (TCR)–peptide–MHC interactions and the peptide–MHC concentration to the degree of T cell activation. This extensive work has produced a wealth of often conflicting data.

  • To make sense of conflicting data, a variety of verbal and mathematical models have been proposed.

  • It is unclear which model or models are consistent and inconsistent with experimental data, as comparisons between the models have been difficult, in part, because they have been formulated in different frameworks.

  • We reformulate published models into five distinct phenotypic models that can be directly compared.

  • We provide figures showing the predicted T cell activation for each model as a function of peptide–MHC concentration and TCR–peptide–MHC binding parameters.

  • We suggest that a kinetic proofreading model that is modified to include limited signalling is consistent with the majority of experimental data but highlight that additional data are required.

Abstract

T cell activation is a crucial checkpoint in adaptive immunity, and this activation depends on the binding parameters that govern the interactions between T cell receptors (TCRs) and peptide–MHC complexes (pMHC complexes). Despite extensive experimental studies, the relationship between the TCR–pMHC binding parameters and T cell activation remains controversial. To make sense of conflicting experimental data, a variety of verbal and mathematical models have been proposed. However, it is currently unclear which model or models are consistent or inconsistent with experimental data. A key problem is that a direct comparison between the models has not been carried out, in part because they have been formulated in different frameworks. For this Analysis article, we reformulated published models of T cell activation into phenotypic models, which allowed us to directly compare them. We find that a kinetic proofreading model that is modified to include limited signalling is consistent with the majority of published data. This model makes the intriguing prediction that the stimulation hierarchy of two different pMHC complexes (or two different TCRs that are specific for the same pMHC complex) may reverse at different pMHC concentrations.

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Figure 1: Relationship between TCR–pMHC binding parameters and T cell activation.
Figure 2: Phenotypic models of T cell activation.
Figure 3: Kinetic proofreading with negative feedback model.
Figure 4: Effects of thresholds and switches in cellular signalling on T cell activation.
Figure 5: Modulation of T cell activation by co-presentation of a second peptide–MHC complex.
Figure 6: Co-presentation of a second pMHC is predicted to inhibit T cell activation in the kinetic proofreading with negative feedback model.

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Acknowledgements

M.L. is supported by a Doctoral Training Centre Systems Biology studentship from the Engineering and Physical Sciences Research Council (EPSRC). O.D. is supported by a Sir Henry Dale Fellowship that is jointly funded by the Wellcome Trust and the Royal Society (grant number 098363). This work was funded in part by Cancer Research UK (C19634/A12336).

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Authors and Affiliations

  1. Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, Oxfordshire, UK

    Melissa Lever, P. Anton van der Merwe & Omer Dushek

  2. Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, OX2 6GG, Oxfordshire, UK

    Philip K. Maini & Omer Dushek

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Glossary

Dissociation time

(τ). The characteristic duration of a T cell receptor–peptide–MHC binding interaction (τ = 1/koff; with typical units of s).

Off-rate

(koff). The rate of T cell receptor–peptide–MHC unbinding (with typical units of s−1).

Potency

(EC50). The concentration or dose of peptide–MHC ligand that produces a half-maximal T cell response (with units provided by the ligand dose).

Dissociation constant

(Kd). The characteristic strength of binding (Kd = koff/kon; with typical units of μM for three-dimensional solution measurements and typical units of μm−2 for two-dimensional membrane measurements).

Maximal efficacy

(Emax). The maximal T cell response achieved at saturating peptide–MHC concentrations (with units provided by the functional assay).

Immunological synapse

A stable region of contact between a T cell and an antigen-presenting cell that forms through the interaction of adhesion molecules on the surface of both cells. The mature immunological synapse contains two distinct stable membrane domains: a central cluster of T cell receptors known as the central supramolecular activation cluster (cSMAC) and a surrounding ring of adhesion molecules known as the peripheral supramolecular activation cluster (pSMAC).

Deterministic model calculations

Mathematical models in which the mean behaviour of a biochemical reaction network is directly calculated, often using ordinary differential equations. All mathematical models in this Analysis article are of this type.

Stochastic model simulations

Mathematical models in which the behaviour of a biochemical reaction network is simulated on the basis of reaction probabilities. Each simulation produces a different result but the mean of many such simulations often (but not always) agrees with the mean that is directly calculated in deterministic models.

Digital signalling

A mode of cellular signalling whereby the concentration of a signalling protein in individual cells is confined to discrete states (for example, all protein is either fully phosphorylated or fully dephosphorylated in a cell). This is in contrast to analogue signalling, in which the concentration of a signalling protein in individual cells is found in a continuum of states.

Altered peptide ligands

(APLs). Peptides that are analogues of an original antigenic peptide. They commonly have amino acid substitutions at residues that make contact with the T cell receptor (TCR). TCR engagement by these APLs usually leads to partial or incomplete T cell activation. Some APLs (antagonists) can specifically antagonize and inhibit T cell activation by the wild-type antigenic peptide.

On-rate

(kon). The rate constant of T cell receptor–peptide–MHC binding (with typical units of μM−1s−1 for three-dimensional solution measurements and typical units of μm2s−1 for two-dimensional membrane measurements).

Slip bonds

Molecular bonds for which the dissociation time decreases under tension.

Catch bonds

Molecular bonds for which the dissociation time increases under tension.

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Lever, M., Maini, P., van der Merwe, P. et al. Phenotypic models of T cell activation. Nat Rev Immunol 14, 619–629 (2014). https://doi.org/10.1038/nri3728

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