The geometry of pMHC‐coated nanoparticles and T‐cell receptor clusters governs the sensitivity‐specificity trade‐off in T‐cell response: a modeling investigation

T cells must reliably discriminate between foreign-derived antigens that require an adaptive immune response and nonspecific self-antigens that do not. This discrimination is highly specific to the affinity of the bond between the ligand and T-cell receptors (TCRs), and highly sensitive to the concentration of ligand. We examined the features of T-cell-mediated immunity in the context of multivalent ligand-receptor interactions between clusters of TCRs with peptide major histocompatibility complex-coated nanoparticles (NPs). Using Monte Carlo simulations of NP-T-cell surface interactions, we compared the effect of TCR clustering on the dose-response curves of bound TCRs when various NP design parameters were altered. These simulations revealed a trade-off between sensitivity and specificity, mediated by TCR clustering and NP geometry. Large TCR clusters enhance sensitivity to both NP valence and NP concentration at the expense of antigen specificity. This loss of specificity arises from two key effects of TCR clustering on NP binding: (1) steric hindrance caused by TCR proximity and NP size, leading to early saturation of bound TCRs; and (2) increased the avidity of multivalent low-affinity NPs. The combination of saturated high-affinity binding and amplified low-affinity binding resulted in impaired affinity-based discrimination. Finally, we demonstrated how kinetic proofreading (KPR) mechanisms mediated by TCR phosphorylation were able to recover specificity in models of T-cell activation. Together, these results suggest that multivalent ligand-receptor interactions promote greater sensitivity at the expense of specificity, and provide mechanistic insights into early T-cell activation that can guide the design of NPs for therapeutic applications.