Interplay between T Cell Receptor Binding Kinetics and the Level of Cognate Peptide Presented by Major Histocompatibility Complexes Governs CD8+ T Cell Responsiveness

Abstract

Background: Adaptive immunity requires T cell receptor (TCR) recognition of antigenic peptide in complex with major histocompatibility complexes (pMHC). Results: Both TCR/pMHC binding kinetics and the amount of interacting cognate pMHC contribute to CD8 ϩ T cell activation.

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

“…A number of studies have reported an optimal pMHC affinity for T-cell activation, but other studies have failed to observe the optimum. Interestingly, a subset of studies have suggested that the optimal pMHC affinity may be less pronounced at high pMHC doses (13,22). The mechanism underlying an optimal pMHC affinity (or half-life) is proposed to be a tradeoff between serial binding and kinetic proofreading, but we have recently shown that this trade-off would lead to an optimal pMHC affinity at all pMHC doses (9).…”

“…Studies performed over the last two decades have focused on empirically mapping the relationship between pMHC affinity and T-cell activation (5,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). A number of studies have reported an optimal pMHC affinity for T-cell activation, but other studies have failed to observe the optimum.…”

T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy

“…In summary, both in vitro and the in vivo antitumor activities of gp209-specific TCRs reach a maximum at a defined avidity and affinity threshold (K D , ∼10μM). Previous studies of the relationship between TCR affinity and T-cell function have led to controversial conclusions (12,17,(22)(23)(24)(25). Here, we demonstrated a plateaued correlation in a self-antigen system in both in vivo and in vitro settings, which has far broader implications for clinical applications.…”

“…Subsequently, efforts have been taken to generate modified high-affinity TCRs for clinical studies (19)(20)(21). However, this correlation remains controversial: high-affinity TCRs have been shown to lead to stronger (22), plateaued (12,17), or even attenuated (23)(24)(25) T-cell responses. Underlying reasons for this controversy could be that antigens previously analyzed were derived from models that induce unusually strong T-cell responses that do not reflect immune responses against true self-antigens, which tend to be less robust.…”

“…Other studies have used a panel of altered peptide ligands in which the lack of correlation between TCR affinity and T-cell activation observed for some peptides could be a result of reduced stability of the peptide-major histocompatibility complexes (pMHCs) over the course of the activation assay (18). Recent work by Rufer and colleagues (17,24) studying T-cell responses and in vitro tumor reactivity to the cancer/testis antigen 1 (NY-ESO-1) showed a plateau of maximal T-cell function at a K D of ∼5 μM but did not determine how the plateau relates to tumor rejection in vivo. Therefore, quantitative analysis of TCR affinity and how it relates to in vivo antitumor activity in ACT is important because it remains unclear whether higher-affinity TCRs can render ACT more effective.…”