Agent-Based Modeling of T Cell Receptor Cooperativity

Abstract Immunological synapse (IS) formation is a key event during antigen recognition by T cells. Recent experimental evidence suggests that the affinity between T cell receptors (TCRs) and antigen is actively modulated during the early steps of TCR signaling. In this work, we used an agent-based model to study possible mechanisms for affinity modulation during IS formation. We show that, without any specific active mechanism, the observed affinity between receptors and ligands evolves over time, and depends on the density of ligand pMHC (antigen peptide presented by major histocompatibility complexes) and TCR molecules. Comparison between the presence or absence of TCR-pMHC centrally directed flow due to F-actin coupling suggest centripetal transport is a potential mechanism for the affinity modulation. The model further suggests that the time point of affinity measurement during immune synapse formation is critical. Finally, a mathematical model of F-actin foci formation incorporated in the agent-based model, shows that TCR affinity can potentially be actively modulated by a positive/negative feedback of F-actin foci on the TCR-pMHC association rate kon.