Human TCR-binding affinity is governed by MHC class restriction

DK Cole, NJ Pumphrey, JM Boulter, M Sami… - The Journal of …, 2007 - journals.aai.org
DK Cole, NJ Pumphrey, JM Boulter, M Sami, JI Bell, E Gostick, DA Price, GF Gao, AK Sewell
The Journal of Immunology, 2007journals.aai.org
T cell recognition is initiated by the binding of TCRs to peptide-MHCs (pMHCs), the
interaction being characterized by weak affinity and fast kinetics. Previously, only 16 natural
TCR/pMHC interactions have been measured by surface plasmon resonance (SPR). Of
these, 5 are murine class I, 5 are murine class II, and 6 are human class I-restricted
responses. Therefore, a significant gap exists in our understanding of human TCR/pMHC
binding due to the limited SPR data currently available for human class I responses and the …
Abstract
T cell recognition is initiated by the binding of TCRs to peptide-MHCs (pMHCs), the interaction being characterized by weak affinity and fast kinetics. Previously, only 16 natural TCR/pMHC interactions have been measured by surface plasmon resonance (SPR). Of these, 5 are murine class I, 5 are murine class II, and 6 are human class I-restricted responses. Therefore, a significant gap exists in our understanding of human TCR/pMHC binding due to the limited SPR data currently available for human class I responses and the absence of SPR data for human class II-restricted responses. We have produced a panel of soluble TCR molecules originating from human T cells that respond to naturally occurring disease epitopes and their cognate pMHCs. In this study, we compare the binding affinity and kinetics of eight class-I-specific TCRs (TCR-Is) to pMHC-I with six class-II-specific TCRs (TCR-IIs) to pMHC-II using SPR. Overall, there is a substantial difference in the TCR-binding equilibrium constants for pMHC-I and pMHC-II, which arises from significantly faster on-rates for TCRs binding to pMHC-I. In contrast, the off-rates for all human TCR/pMHC interactions fall within a narrow window regardless of class restriction, thereby providing experimental support for the notion that binding half-life is the principal kinetic feature controlling T cell activation.
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