Fluctuations in TCR and pMHC interactions regulate T cell activation

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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Identifiers

ORCID for Joseph, Robert Egan: orcid.org/0000-0002-6414-1334

ORCID for Timothy Elliott: orcid.org/0000-0003-1097-0222

ORCID for Benjamin Macarthur: orcid.org/0000-0002-5396-9750

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