The dimeric cell-surface glycoprotein CD8 is crucial to the positive selection of cytotoxic T cells in the thymus1. The homodimer CD8αα or the heterodimer αβ stabilizes the interaction of the T-cell antigen receptor (TCR) with major histocompatibility complex (MHC) class I/peptide by binding to the class I molecule2. Here we report the crystal structure at 2.7Å resolution of a complex between CD8αα and the human MHC molecule HLA-A2, which is associated with peptide. CD8αα binds one HLA-A2/peptide molecule, interfacing with the α2 and α3 domains of HLA-A2 and also contacting β2-microglobulin. A flexible loop of the α3 domain (residues 223–229) is clamped between the complementarity-determining region (CDR)-like loops of the two CD8 subunits in the classic manner of an antibody–antigen interaction, precluding the binding of a second MHC molecule. The position of the α3 domain is different from that in uncomplexed HLA-A2 (refs 3, 4), being most similar to that in the TCR/Tax/HLA-A2 complex5, but no conformational change extends to the MHC/peptide surface presented for TCR recognition. Although these shifts in α3 may provide a synergistic modulation of affinity, the binding of CD8 to MHC is clearly consistent with an avidity-based contribution from CD8 to TCR–peptide–MHC interactions.
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We are grateful to the late Alan Williams for discussions that inspired this work. We thank R. Bryan, K. Measures and R. Esnouf for computing facilities and programs; K. Harlos for assistance with X-ray data collection, S. Lee for help in the preparation of figures; Z. Rao for assistance in crystallization trials; D. Wiley and D. Garboczi for pre-release coordinates of the TCR/Tax/HLA-A2 complex; and C. O'Callahan, V. Cerundolo, D. Garboczi, G. Harcourt and B. Willcox for help and advice. This work was funded by the MRC. The Oxford Centre for Molecular Sciences is supported by the BBSRC, EPSRC and MRC. J.T. was supported by an EMBO fellowship, E.Y.J. by the Royal Society, and D.I.S. and A.J.M. by the MRC.
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Gao, G., Tormo, J., Gerth, U. et al. Crystal structure of the complex between human CD8αα and HLA-A2. Nature 387, 630–634 (1997). https://doi.org/10.1038/42523
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