Structural Basis of CD160:HVEM Recognition

Structure. 2019 Aug 6;27(8):1286-1295.e4. doi: 10.1016/j.str.2019.05.010. Epub 2019 Jun 20.


CD160 is a signaling molecule that interacts with herpes virus entry mediator (HVEM) and contributes to a wide range of immune responses, including T cell inhibition, natural killer cell activation, and mucosal immunity. GPI-anchored and transmembrane isoforms of CD160 share the same ectodomain responsible for HVEM engagement, which leads to bidirectional signaling. Despite the importance of the CD160:HVEM signaling axis and its therapeutic relevance, the structural and mechanistic basis underlying CD160-HVEM engagement has not been described. We report the crystal structures of the human CD160 extracellular domain and its complex with human HVEM. CD160 adopts a unique variation of the immunoglobulin fold and exists as a monomer in solution. The CD160:HVEM assembly exhibits a 1:1 stoichiometry and a binding interface similar to that observed in the BTLA:HVEM complex. Our work reveals the chemical and physical determinants underlying CD160:HVEM recognition and initiation of associated signaling processes.

Keywords: CD160 and HVEM; IgSF and TNFRSF interactions; Interaction promiscuity; T cell costimulation and coinhibition; X-ray structures; immune regulation; intermolecular beta-sheet.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antigens, CD / chemistry*
  • Antigens, CD / metabolism*
  • Binding Sites
  • Crystallography, X-Ray
  • GPI-Linked Proteins / chemistry
  • GPI-Linked Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Protein Binding
  • Protein Conformation, beta-Strand
  • Protein Domains
  • Protein Folding
  • Receptors, Immunologic / chemistry*
  • Receptors, Immunologic / metabolism*
  • Receptors, Tumor Necrosis Factor, Member 14 / chemistry*
  • Receptors, Tumor Necrosis Factor, Member 14 / metabolism*


  • Antigens, CD
  • BTLA protein, human
  • CD160 protein, human
  • GPI-Linked Proteins
  • Receptors, Immunologic
  • Receptors, Tumor Necrosis Factor, Member 14
  • TNFRSF14 protein, human