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A conserved energetic footprint underpins recognition of human leukocyte antigen-E by two distinct αβ T cell receptors

Sullivan, Lucy C., Walpole, Nicholas G., Farenc, Carine, Pietra, Gabriella, Sum, Matthew J. W., Clements, Craig S., Lee, Eleanor J., Beddoe, Travis, Falco, Michela, Mingari, Maria Cristina, Moretta, Lorenzo, Gras, Stephanie, Rossjohn, Jamie and Brooks, Andrew G. 2017. A conserved energetic footprint underpins recognition of human leukocyte antigen-E by two distinct αβ T cell receptors. Journal of Biological Chemistry 292 (51) , pp. 21149-21158. 10.1074/jbc.M117.807719

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Abstract

αβ T cell receptors (TCRs) interact with peptides bound to the polymorphic major histocompatibility complex class Ia (MHC-Ia) and class II (MHC-II) molecules as well as the essentially monomorphic MHC class Ib (MHC-Ib) molecules. Although there is a large amount of information on how TCRs engage with MHC-Ia and MHC-II, our understanding of TCR/MHC-Ib interactions is very limited. Infection with cytomegalovirus (CMV) can elicit a CD8+ T cell response restricted by the human MHC-Ib molecule human leukocyte antigen (HLA)-E and specific for an epitope from UL40 (VMAPRTLIL), which is characterized by biased TRBV14 gene usage. Here we describe an HLA-E–restricted CD8+ T cell able to recognize an allotypic variant of the UL40 peptide with a modification at position 8 (P8) of the peptide (VMAPRTLVL) that uses the TRBV9 gene segment. We report the structures of a TRBV9+ TCR in complex with the HLA-E molecule presenting the two peptides. Our data revealed that the TRBV9+ TCR adopts a different docking mode and molecular footprint atop HLA-E when compared with the TRBV14+ TCR–HLA-E ternary complex. Additionally, despite their differing V gene segment usage and different docking mechanisms, mutational analyses showed that the TCRs shared a conserved energetic footprint on the HLA-E molecule, focused around the peptide-binding groove. Hence, we provide new insights into how monomorphic MHC molecules interact with T cells.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Date of First Compliant Deposit: 26 January 2018
Date of Acceptance: 24 August 2017
Last Modified: 31 Jan 2018 14:24
URI: http://orca-mwe.cf.ac.uk/id/eprint/108515

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