T cell receptor recognition of a 'super-bulged' major histocompatibility complex class I–bound peptide

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Abstract

Unusually long major histocompatibility complex (MHC) class I–restricted epitopes are important in immunity, but their 'bulged' conformation represents a potential obstacle to αβ T cell receptor (TCR)–MHC class I docking. To elucidate how such recognition is achieved while still preserving MHC restriction, we have determined here the structure of a TCR in complex with HLA-B*3508 presenting a peptide 13 amino acids in length. This complex was atypical of TCR–peptide–MHC class I interactions, being dominated at the interface by peptide-mediated interactions. The TCR assumed two distinct orientations, swiveling on top of the centrally bulged, rigid peptide such that only limited contacts were made with MHC class I. Although the TCR-peptide recognition resembled an antibody-antigen interaction, the TCR–MHC class I contacts defined a minimal 'generic footprint' of MHC-restriction. Thus our findings simultaneously demonstrate the considerable adaptability of the TCR and the 'shape' of MHC restriction.

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Figure 1: Overview of the SB27 TCR in complex with HLA-B*3508–LPEP.
Figure 2: SB27 TCR contacts at the interface.
Figure 3: The SB27 CTL clone is both MHC restricted and alloreactive with HLA-B*4402, with which it shares structural features in the region of the TCR footprint.
Figure 4: SB27 TCR recognition of the HLA-B*3508–LPEP complex is antibody like and is dominated by TCR-peptide interactions.
Figure 5: The SB27 TCR–HLA-B*3508–LPEP complex forms a TCR 'superdimer' with two subtly different TCR–pMHC-I orientations.

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Acknowledgements

We thank A. Brooks and D. El-hassen for discussions and reagents; P. Doherty, F. Carbone and S. Turner for critical reading of the manuscript; and the BioCars staff for assistance in data collection at Advanced Photon Source (Chicago, Illinois). J.R. and J.M. are joint senior authors. Supported by the National Health and Medical Research Council Australia, Roche Organ Transplantation Research Fund, Australian Research Council, National Health and Medical Research Council Career Development Award (S.B.), National Health and Medical Research Council Peter Doherty Training Fellowship (T.B.) and Wellcome Trust (J.R.).

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Correspondence to James McCluskey or Jamie Rossjohn.

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Supplementary information

Supplementary Table 1

Contacts at the TCD-pMHC interface for complex B. (PDF 108 kb)

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