Comparing kinetic proofreading and kinetic segregation for T cell receptor activation

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 in silico. 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.