T‐cell receptor binding affinities and kinetics: impact on T‐cell activity and specificity

Abstract

SummaryThe interaction between the T-cell receptor (TCR) and its peptide-major histocompatibility complex (pepMHC) ligand plays a critical role in determining the activity and specificity of the T cell. The binding properties associated with these interactions have now been studied in many systems, providing a framework for a mechanistic understanding of the initial events that govern T-cell function. There have been various other reviews that have described the structural and biochemical features of TCR : pepMHC interactions. Here we provide an overview of four areas that directly impact our understanding of T-cell function, as viewed from the perspective of the TCR : pepMHC interaction: (1) relationships between T-cell activity and TCR : pepMHC binding parameters, (2) TCR affinity, avidity and clustering, (3) influence of coreceptors on pepMHC binding by TCRs and T-cell activity, and (4) impact of TCR binding affinity on antigenic peptide specificity.

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

“…Previous studies (16,41) indicate that the contribution of CD8 to TCR/pMHC interaction is dependent on ligand C B A affinity. However, it is unknown whether the properties of TCRs can determine the magnitude of CD8 contribution (29). It has been demonstrated that CD8 engages in the TCR/pMHC interaction in the second stage after the TCR/pMHC complex is formed (41).…”

“…The affinities of the TCRs, as measured the by surface plasmon resonance (SPR) ( Table 1 and Fig. S1), span the entire affinity range of naturally selected TCRs (K D , ∼1-100 μM) (29) and thus provide a suitable system for studying the correlation between TCR affinity and functional activities. To investigate the antitumor activities of the TCRs, we characterized them in primary splenocytes isolated from A2-K b transgenic mice (38), a model for studying HLA-A2-restricted TCRs (35,39).…”

“…Together, these results highlight the contribution of CD8 to the TCR/pMHC interaction, which in some cases can be dependent on individual TCR structure. TCR avidity is affected by cellular environments and coreceptors in addition to TCR affinity (29).…”

“…The strength of the TCR/pMHC interaction on the cell surface is determined not only by TCR affinity, but also by other factors, such as TCR clustering and coreceptors (29). Coreceptors stabilize TCR/pMHC interactions and are required for functionality of low-affinity TCRs (16).…”

“…Coreceptors stabilize TCR/pMHC interactions and are required for functionality of low-affinity TCRs (16). pMHC tetramers (6,14,16,30) have been used to measure the combined effects, which is referred to as avidity (29). Tetramer-based avidity measurements should not be confused with T-cell functional avidity (10,11,31), which refers to cellular responses in addition to binding.…”