CD8+ T Cell Activation Is Governed by TCR-Peptide/MHC Affinity, Not Dissociation Rate

Abstract

Binding of peptide/MHC (pMHC) complexes by TCR initiates T cell activation. Despite long interest, the exact relationship between the biochemistry of TCR/pMHC interaction (particularly TCR affinity or ligand off-rate) and T cell responses remains unresolved, because the number of complexes examined in each independent system has been too small to draw a definitive conclusion. To test the current models of T cell activation, we have analyzed the interactions between the mouse P14 TCR and a set of altered peptides based on the lymphocytic choriomeningitis virus epitope gp33–41 sequence bound to mouse class I MHC Db. pMHC binding, TCR-binding characteristics, CD8+ T cell cytotoxicity, and IFN-γ production were measured for the peptides. We found affinity correlated well with both cytotoxicity and IFN-γ production. In contrast, no correlation was observed between any kinetic parameter of TCR-pMHC interaction and cytotoxicity or IFN-γ production. This study strongly argues for an affinity threshold model of T cell activation.

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.…”

“…T-cell functional activity is determined by avidity, which is mainly determined by TCR affinity. A plateau of T-cell functional activity above a defined affinity threshold has been reported (12,17). Here we show that one possible explanation for this phenomenon is the diminishing contribution of TCR affinity to avidity on the cell surface above a defined threshold.…”

“…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.…”

“…To this end, it is critical to determine what TCR properties correlate to antitumor activity. Substantial evidence indicates a correlation between T-cell functional activity and TCR affinity (12)(13)(14)(15)(16)(17)(18). Subsequently, efforts have been taken to generate modified high-affinity TCRs for clinical studies (19)(20)(21).…”

To affinity and beyond: Harnessing the T Cell receptor for cancer immunotherapy

“…9,10 A second proposal marked the idea that the number of TCR-pMHC interactions, as a function of affinity for antigen and ligand density, was determinant of T cell activation levels. 11 Further work showed that TCR affinity for pep:MHC may regulate the type of signal generated and subsequent progeny produced. 12 High affinity TCRs interact long enough with pep-MHC to allow an asymmetric generation of daughter T cells and subsequent development of short-lived effector cells (SLECs).…”