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Front. Immunol. | doi: 10.3389/fimmu.2019.00349

Is TCR/pMHC affinity a good estimate of the T-cell response? An answer based on predictions from twelve phenotypic models

 Jesus Galvez1, 2*, Juan J. Gálvez3 and  Pilar Garcia-Peñarrubia1
  • 1University of Murcia, Spain
  • 2Departamento de Química Física, Facultad de Química, Universidad de Murcia, Spain
  • 3Department of Computer Science, University of Illinois at Urbana-Champaign, United States

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 twelve 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 kof 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.

Keywords: T-cell activation, TCR/pMHC, TCR-pMHC interaction, Affinity, correlation between affinity and immune response, phenotypic models, T-cell response

Received: 30 Aug 2018; Accepted: 11 Feb 2019.

Edited by:

Francisco Sanchez-Madrid, Autonomous University of Madrid, Spain

Reviewed by:

Balbino Alarcon, Spanish National Research Council (CSIC), Spain
Mario Castro, Comillas Pontifical University, Spain  

Copyright: © 2019 Galvez, Gálvez and Garcia-Peñarrubia. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Jesus Galvez, University of Murcia, Murcia, Spain, jgalvez@um.es