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Human TCR-Binding Affinity is Governed by MHC Class Restriction¹

David K. Cole^*,, Nicholas J. Pumphrey, Jonathan M. Boulter, Malkit Sami, John I. Bell^*, Emma Gostick^*, David A. Price^*, George F. Gao^*,, Andrew K. Sewell^*, and Bent K. Jakobsen^2,

^* Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; Avidex Limited, Abingdon, Oxon, United Kingdom; Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, United Kingdom; and Center for Molecular Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, People’s Republic of China

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ D.K.C. was supported by a Medical Research Council (MRC) (U.K.) studentship. G.F.G. was supported by Chinese Academy of Sciences Knowledge Innovation Project Grant No. KSCX2-SW-227. J.M.B. was supported by a Research Councils UK academic fellowship. D.A.P. is an MRC Senior Clinical Fellow; A.K.S. is a Wellcome Trust Senior Fellow.

² Address correspondence and reprint requests to Dr. Bent K. Jakobsen, Avidex Limited, 57C Milton Park, Abingdon, Oxon, OX14 4RX, U.K. E-mail address: bent.jakobsen{at}avidex.com

³ Abbreviations used in this paper: pMHC, peptide-MHC; MHC-I, MHC class I; MHC-II, MHC class II; ₂m, ₂-microglobulin; SPR, surface plasmon resonance; MBP, myelin basic protein.