Theoretical quantification of the polyvalent binding of nanoparticles coated with peptide-major histocompatibility complex to T cell receptor-nanoclusters.

Abstract

Nanoparticles (NPs) coated with peptide-major histocompatibility complexes (pMHCs) can be used as a therapy to treat autoimmune diseases. They do so by inducing the differentiation and expansion of disease-suppressing T regulatory type 1 (Tr1) cells by binding to their T cell receptors (TCRs) expressed as TCR-nanoclusters (TCRnc). Their efficacy can be controlled by adjusting NP size and number of pMHCs coated on them (referred to as valence). The binding of these NPs to TCRnc on T cells is thus polyvalent and occurs at three levels: the TCR-pMHC, NP-TCRnc and T cell levels. In this study, we explore how this polyvalent interaction is manifested and examine if it can facilitate T cell activation downstream. This is done by developing a multiscale biophysical model that takes into account the three levels of interactions and the geometrical complexity of the binding. Using the model, we quantify several key parameters associated with this interaction analytically and numerically, including the insertion probability that specifies the number of remaining pMHC binding sites in the contact area between T cells and NPs, the dwell time of interaction between NPs and TCRnc, carrying capacity of TCRnc, the distribution of covered and bound TCRs, and cooperativity in the binding of pMHCs within the contact area. The model was fit to previously published dose-response curves of interferon-γ obtained experimentally by stimulating a population of T cells with increasing concentrations of NPs at various valences and NP sizes. Exploring the parameter space of the model revealed that for an appropriate choice of the contact area angle, the model can produce moderate jumps between dose-response curves at low valences. This suggests that the geometry and kinetics of NP binding to TCRnc can act in synergy to facilitate T cell activation.