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The T cell receptor (TCR) is a key component of the adaptive immune system, recognizing foreign antigens (ligands) and triggering an immune response. To explain the high sensitivity and selectivity of the TCR in discriminating “self” from “non-self” ligands, most models evoke kinetic proofreading (KP) schemes, however it is unclear how competing models used for TCR triggering, such as the kinetic segregation (KS) model, influence KP performance. In this paper, we consider two different TCR triggering models and their influence on subsequent KP-based ligand discrimination by the TCR: a classic conformational change model (CC-KP), where ligand-TCR binding is strictly required for activation, and the kinetic segregation model (KS-KP), where only residence of the TCR within a close contact devoid of kinases is required for its activation. Building on previous work, our computational model permits a head-to-head comparison of these models . While we find that both models can be used to explain the probability of TCR activation across much of the parameter space, we find biologically important regions in the parameter space where significant differences in performance can be expected. Furthermore, we show that the available experimental evidence may favor the KS-KP model over CC-KP. Our results may be used to motivate and guide future experiments to determine accurate mathematical models of TCR function. Published by the American Physical Society2025 

The T cell receptor (TCR) initiates the elimination of pathogens and tumors by T cells. To avoid damage to the host, the receptor must be capable of discriminating between wild-type and mutated self and nonself peptide ligands presented by host cells. Exactly how the TCR does this is unknown. In resting T cells, the TCR is largely unphosphorylated due to the dominance of phosphatases over the kinases expressed at the cell surface. However, when agonist peptides are presented to the TCR by major histocompatibility complex proteins expressed by antigen-presenting cells (APCs), very fast receptor triggering, i.e., TCR phosphorylation, occurs. Recent work suggests that this depends on the local exclusion of the phosphatases from regions of contact of the T cells with the APCs. Here, we developed and tested a quantitative treatment of receptor triggering reliant only on TCR dwell time in phosphatase-depleted cell contacts constrained in area by cell topography. Using the model and experimentally derived parameters, we found that ligand discrimination likely depends crucially on individual contacts being ∼200 nm in radius, matching the dimensions of the surface protrusions used by T cells to interrogate their targets. The model not only correctly predicted the relative signaling potencies of known agonists and nonagonists but also achieved this in the absence of kinetic proofreading. Our work provides a simple, quantitative, and predictive molecular framework for understanding why TCR triggering is so selective and fast and reveals that, for some receptors, cell topography likely influences signaling outcomes.