Fluctuations in T cell receptor 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.

Ligand induced receptor multimerization achieves the specificity enhancement of kinetic proofreading without associated costs

“…Although the values of g can vary substantially between different systems, typically for cell signaling receptors R T ∼ 100 − 1000, although inter-cellular distributions can have long tails; k off ∼ 0.001 − 1 sec −1 ; and k f ∼ 0.1µm 2 /(molecules • sec) yielding g ∼ 0.01 − 100 [5,71,72]. As an example, the Type I Interferon receptor -a heterodimer -operates at approximately g ≈ 1 to 10, with a substantial specificity enhancement (see Table S1).…”

“…Intrinsic stochasticity of the reaction kinetics in both the KPR and multimer models leads to variance in the receptor output, which can significantly limit the accuracy of downstream signal processing [1,11,31,36,57,59,69,72,79]. Such noise affects the precision of ligand identification and classification [10,36,69], accuracy of decision making with many possible responses (sometimes referred to as functional plasticity) [3,5,43], and the identification and disentanglement of mixtures of ligands presented to the receptor [69,[80][81][82][83].…”

Force-Induced Site-Specific Enzymatic Cleavage Probes Reveal That Serial Mechanical Engagement Boosts T Cell Activation

“…Another prominent model that helps explain TCR sensitivity is the serial engagement model which postulates that TCRs repeatedly engage stimulatory pMHCs to trigger activation at low antigen density. − Kalergis et al have demonstrated a “Goldilocks-like” relationship between the TCR-pMHC dwell time and T cell activation . If dwell times are too short, then the TCRs fail to initiate signaling.…”