Fluctuations in T cell receptor and pMHC interactions regulate T cell activation

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.