Human TCR-binding affinity is governed by MHC class restriction.
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.
Cole
David K
DK
Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
Pumphrey
Nicholas J
NJ
Boulter
Jonathan M
JM
Sami
Malkit
M
Bell
John I
JI
Gostick
Emma
E
Price
David A
DA
Gao
George F
GF
Sewell
Andrew K
AK
Jakobsen
Bent K
BK
D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D007700:Kinetics; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000276:immunology; D020349:Surface Plasmon Resonance
D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D011948:Receptors, Antigen, T-Cell