Structural basis for a major histocompatibility complex class Ib–restricted T cell response

Abstract

In contrast to antigen-specific immunity orchestrated by major histocompatibility complex (MHC) class Ia molecules, the ancestrally related nonclassical MHC class Ib molecules generally mediate innate immune responses. Here we have demonstrated the structural basis by which the MHC class Ib molecule HLA-E mediates an adaptive MHC-restricted cytotoxic T lymphocyte response to human cytomegalovirus. Highly constrained by host genetics, the response showed notable fine specificity for position 8 of the viral peptide, which is the sole discriminator of self versus nonself. Despite the evolutionary divergence of MHC class Ia and class Ib molecules, the structure of the T cell receptor–MHC class Ib complex was very similar to that of conventional T cell receptor–MHC class Ia complexes. These results emphasize the evolutionary 'ambiguity' of HLA-E, which not only interacts with innate immune receptors but also has the functional capacity to mediate virus-specific cytotoxic T lymphocyte responses during adaptive immunity.

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Figure 1: Flow cytometry of CMV-specific cells from the CMV-seronegative donor RC (HLA-A2,HLA-A29, HLA-B44, HLA-B51 and HLA-Cw7) and the CMV-seropositive donor KK (HLA-A2, HLA-B44 and HLA-Cw7).
Figure 2: Low-affinity interaction between HLA-E–(VMAPRTLIL) and the TCR.
Figure 3: The KK50.4 TCR–HLA-E–(VMAPRTLIL) complex.
Figure 4: Contribution of CDRs to the 'footprint' of the KK50.4 TCR on HLA-E–(VMAPRTLIL).
Figure 5: KK50.4 TCR–peptide interactions are dominated by the Vβ loops.
Figure 6: Residues unique to HLA-E form the basis of the restriction of KK50.4 to HLA-E.

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Acknowledgements

We thank P. Coulie for HLA-E tetramers; A. Purcell for critical reading of the manuscript; and the Biocars staff at Advanced Photon Source (Chicago, Illinois) for assistance with data collection. Supported by the National Health and Medical Research Council, Doherty Fellowships from the National Health and Medical Research Council (L.C.S. and T.B.), the Australian Research Council, an Australian Research Council Professorial Fellowship (J.R.) and a Wellcome Trust Senior Research Fellowship in Biomedical Science (J.R.).

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Correspondence to Jamie Rossjohn or Andrew G Brooks.

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Hoare, H., Sullivan, L., Pietra, G. et al. Structural basis for a major histocompatibility complex class Ib–restricted T cell response. Nat Immunol 7, 256–264 (2006). https://doi.org/10.1038/ni1312

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