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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Authors updated to include two new authors; Author Affiliations updated to include recent positions; Introduction updated to provide an improved explanation of the potential mechanisms that contribute to T cell activation; Results (section 3) significantly updated to provide details of additional experimental data-sets that are consistent with our theory; Discussion updated to provide an improved explanation of how our model compares with other models of T cell activation in the literature; Methods updated to include experimental details of the previously unpublished data shown in Figure 4; Figure 1 revised to show how mechanisms can potentially generate an activating T cell signal; Figure 2 revised to explicitly state the parameter values used in each simulation; Figure 3 revised to clarify the labels on the y-axis; Figure 4 added to show exemplar data-sets that are consistent with theory; Table 1 added to show a summary of the parameter-values described in the literature that were adapted for our model parametrization; Supplementary Information (sections 2.2 and 2.3) updated to provide an explanation for the connection between Shannon entropy and variance; Supplementary Information (section 5) significantly updated to provide a similar alternative minimal model of T cell activation.
