T cell receptor binding kinetics required for T cell activation depend on the density of cognate ligand on the antigen-presenting cell

Abstract

CD8 ؉ T cells recognize peptides of eight to nine amino acid residues long in the context of MHC class I molecules on the surface of antigen-presenting cells (APCs). This recognition event is highly sensitive, as evidenced by the fact that T cells can be activated by cognate peptide͞MHC complex (pMHC) at extremely low densities (1-50 molecules). High sensitivity is particularly valuable for detection of antigens at low density, such as those derived from tumor cells and intracellular pathogens, which can down-modulate cognate pMHCs from the surface of APCs to evade recognition by the adaptive immune system. T cell activation is only triggered in response to interactions between the T cell receptor (TCR) and the pMHC ligand that reach a specific half-life threshold. However, interactions with excessively long half-lives result in impaired T cell activation. Thus, efficient T cell activation by pMHC on the surface of APCs requires an optimal dwell time of TCR-pMHC interaction. Here, we show that, although this is a requirement at low cognate pMHC density on the APC surface, at high epitope density there is no impairment of T cell activation by extended TCR-pMHC dwell times. This observation was predicted by mathematical simulations for T cell activation by pMHC at different densities and supported by experiments performed on APCs selected for varied expression of cognate pMHC. According to these results, effective T cell activation depends on a complex interplay between inherent TCR-pMHC binding kinetics and the epitope density on the APC.

T-cell antagonism by short half-life pMHC ligands can be mediated by an efficient trapping of T-cell polarization toward the APC

“…S1). These data are consistent with previous observations made in different TCR/pMHC systems (6)(7)(8)10). …”

“…However the first-order binding of the pMHC to the TCR is still longer for the G4 peptide than for the pOVA as measured by Biacore (14,27). This notion is consistent with the partial T-cell activation observed in response to high pOVA-G4 peptide concentrations, because as previously shown, long half-life pMHC ligands can induce T-cell activation when they are at high density on the APC surface (8). Nevertheless, data from tetramer dissociation and potency in thymic selection assays suggest that the G4 ligand is intermediate in half-life and potency between OVA and E1 (51).…”

“…Furthermore, to determine T-cell Golgi polarization in response to long half-lives of TCR/pMHC interactions, a variant of the N30.7 TCR carrying a point mutation in the CDR3β (G99A) showing a longer half-life for the H-2K b /VSV complex than the WT N30.7 TCR (Table S3) (8,10) was used to complement the data obtained with the G4 ligand. As shown in Fig.…”

“…Several kinetic requirements must be satisfied by the TCR/ pMHC interaction to efficiently induce T-cell activation (6)(7)(8)(9)(10)(11)(12)(13). The half-life (t 1/2 ) of the TCR/pMHC interaction must be above certain threshold to allow productive TCR signaling, as proposed by the kinetic proofreading model (11).…”

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

“…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.…”