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

Lucy C. Sullivan, Nicholas G. Walpole, Carine Farenc, Gabriella Pietra, Matthew J.W. Sum, Craig S. Clements, Eleanor J. Lee, Travis Beddoe, Michela Falco, Maria Cristina Mingari, Lorenzo Moretta, Stephanie Gras, Jamie Rossjohn, Andrew G. Brooks

Research output: Contribution to journalArticle

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 CD8Tcell 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.Wereport the structures of aTRBV9TCRin complex with the HLA-E molecule presenting the two peptides. Our data revealed that the TRBV9+TCRadopts 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 intohowmonomorphicMHCmolecules interact withT cells.

Original languageEnglish
Pages (from-to)21149-21158
Number of pages10
JournalJournal of Biological Chemistry
Volume292
Issue number51
DOIs
Publication statusPublished - Jan 1 2017

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Sullivan, L. C., Walpole, N. G., Farenc, C., Pietra, G., Sum, M. J. W., Clements, C. S., Lee, E. J., Beddoe, T., Falco, M., Mingari, M. C., Moretta, L., Gras, S., Rossjohn, J., & Brooks, A. 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), 21149-21158. https://doi.org/10.1074/jbc.M117.807719