T cell receptor signal transduction: affinity, force and conformational change

Moogk, Duane; Natarajan, Aswin; Krogsgaard, Michelle

doi:10.1016/j.coche.2017.12.007

Cited by 4 publications

(1 citation statement)

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“…This section provides a brief description of the phenotypic models (a)-(l) used in this work, their mathematical assumptions, and their levels of complexity, bearing in mind that models (h)-(k) are new models which have not been previously described in the literature. The reader interested in more details on the problems discussed in this section can consult the review articles ( 3 , 4 , 47 , 48 ) and references ( 14 , 49 – 52 ). Also, the following considerations should be taken into account: (a) in general, quantitative predictions from a given model rely on the premises on which the model is built.…”

Section: Methodsmentioning

confidence: 99%

Is TCR/pMHC Affinity a Good Estimate of the T-cell Response? An Answer Based on Predictions From 12 Phenotypic Models

Gálvez

García‐Peñarrubia

2019

Front. Immunol.

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On the T-cell surface the TCR is the only molecule that senses antigen, and the engagement of TCR with its specific antigenic peptide (agonist)/MHC complex (pMHC) is determined by the biochemical parameters of the TCR-pMHC interaction. This interaction is the keystone of the adaptive immune response by triggering intracellular signaling pathways that induce the expression of genes required for T cell-mediated effector functions, such as T cell proliferation, cytokine secretion and cytotoxicity. To study the TCR-pMHC interaction one of its properties most extensively analyzed has been TCR-pMHC affinity. However, and despite of intensive experimental research, the results obtained are far from conclusive. Here, to determine if TCR-pMHC affinity is a reliable parameter to characterize T-cell responses, a systematic study has been performed based on the predictions of 12 phenotypic models. This approach has the advantage that allow us to study the response of a given system as a function of only those parameters in which we are interested while other system parameters remain constant. A little surprising, only the simple occupancy model predicts a direct relationship between affinity and response so that an increase in affinity always leads to larger responses. Conversely, in the others more elaborate models this clear situation does not occur, i.e., that a general positive correlation between affinity and immune response does not exist. This is mainly because affinity values are given by the quotient kon/koff where kon and koff are the rate constants of the binding process (i.e., affinity is in fact the quotient of two parameters), so that different sets of these rate constants can give the same value of affinity. However, except in the occupancy model, the predicted T-cell responses depend on the individual values of kon and koff rather than on their quotient kon/koff. This allows: a) that systems with the same affinity can show quite different responses; and b) that systems with low affinity may exhibit larger responses than systems with higher affinities. This would make affinity a poor estimate of T-cell responses and, as a result, data correlations between affinity and immune response should be interpreted and used with caution.

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