An information-theoretic model of T cell activation

Abstract

Adaptive immune responses depend on the interactions between T cell receptors
(TCRs) and peptide major-histocompatibility complex (pMHC) ligands located on the surface of T cells and antigen presenting cells, respectively. There is increasing evidence that TCRs and pMHC ligands at the T cell-APC contact area are often present at low copy-numbers. Consequently, their interactions are inherently stochastic meaning that the number of bound pMHC-TCR complexes can fluctuate rapidly.
However, the role of these stochastic fluctuations on T cell function is unclear. In this thesis a number of stochastic properties associated with the pMHC-TCR interactions are derived. It is shown that a combination of the magnitude and rate of the stochastic fluctuations, as quantified by the entropy rate, is consistent with a wide variety of experimental data. In addition, a minimal stochastic model is developed to illustrate the concept that three experimentally observed TCR-proximal mechanisms can transmit a signal to the T cell nucleus at a rate that approximates the entropy rate.

Taking an information theoretic perspective, the entropy rate represents the average rate at which antigen-specific information is conveyed to the T cell from an APC. This suggests that it is not the strength of binding between the T cell and APC per se that elicits an immune response, but rather the rate at which information is imparted to the T cell from the encounter. It is therefore proposed that the adaptive immune response is regulated by the entropy rate of the pMHC-TCR interactions. Optimising the entropy rate via modification of its parameters could improve the efficacy of T cell immunotherapies that are designed to treat cancer. In particular, the optimal 2D dissociation constant, Kd is approximately equal to half the greater of the TCR and pMHC ligand copy-numbers. Furthermore, faster pMHC-TCR interactions that maintain the optimal Kd result in higher entropy rates and, therefore, larger predicted T cell responses. The simplicity of the model developed here means that an information-theoretic perspective of receptor-ligand binding could have application to a wide range of other therapeutics.

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Identifiers

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

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