The geometry of pMHC-coated nanoparticles and T cell receptor clusters governs the sensitivity-specificity trade-off in T cell response.

T cells must reliably discriminate between foreign-derived antigens that require an adaptive immune response from non-specific self-antigens that do not. This discrimination is highly specific to the affinity of the bond between ligand and T cell receptors (TCRs), as well as highly sensitive to the concentration of ligand. In this study, we examined these features of T cell mediated immunity in the context of multivalent ligand-receptor interactions between clusters of TCRs with pMHC-coated nanoparticles (NPs). Using Monte Carlo simulations of NP-T cell surface interactions, we compared the effect of TCR clustering on the dose-response profiles of various NP designs. These simulations revealed a trade-off between sensitivity and specificity, mediated by the spatial clustering of TCRs and the geometry of the NP. In particular, large clusters of TCRs were more sensitive to both NP valence and ligand concentration at the expense of antigen specificity. Conversely, uniformly distributed TCR landscapes were better suited to affinity-based ligand discrimination, while sacrificing sensitivity to ligand concentration. These features of NP-mediated T cell activation depended significantly on NP size and valence rather than on the average ligand concentration. Furthermore, we demonstrated how kinetic proofreading mechanisms may help compensate for the limitations associated with TCR clustering. These findings thus highlight the importance of interacting geometries of NP design and TCR landscape in modulating the specificity and sensitivity of the T cell response. SignificanceT cells rely on surface T cell receptors (TCRs) to recognize foreign antigens presented as peptide-major histocompatibility complex (pMHC) molecules. TCR clustering is crucial for T cell activation, though its full role remains not entirely clear. Using Monte Carlo simulations, we demonstrate that TCR clustering profoundly influences both surface binding dynamics of multivalent pMHC-coated nanoparticles, used in autoimmune disease therapies, as well as downstream intracellular signals leading to T cell activation. Our findings thus provide important insights into the role of interaction geometries in shaping T cell response, with implications for optimizing nanoparticle design to enhance their therapeutic efficacy.