Evolutionarily divergent herpesviruses modulate T cell activation by targeting the herpesvirus entry mediator cosignaling pathway

Timothy C. Cheung, Ian R. Humphreys, Karen G. Potter, Paula S. Norris, Heather M. Shumway, Bonnie R. Tran, Ginelle Patterson, Rochelle Jean-Jacques, Miri Yoon, Patricia G. Spear, Kenneth M. Murphy, Nell S. Lurain, Chris A. Benedict, Carl F. Ware

Research output: Contribution to journalArticlepeer-review

165 Scopus citations

Abstract

The herpesvirus entry mediator (HVEM), a member of the TNF receptor (TNFR) super-family, can act as a molecular switch that modulates T cell activation by propagating positive signals from the TNF-related ligand LIGHT (TNFR super-family 14), or inhibitory signals through the Ig super-family member B and T lymphocyte attenuator (BTLA). Competitive binding analysis and mutagenesis reveals a unique BTLA binding site centered on a critical lysine residue in cysteine-rich domain 1 of HVEM. The BTLA binding site on HVEM overlaps with the binding site for the herpes simplex virus 1 envelope glycoprotein D, but is distinct from where LIGHT binds, yet glycoprotein D inhibits the binding of both ligands, potentially nullifying the pathway. The binding site on HVEM for BTLA is conserved in the orphan TNFR, UL144, present in human CMV. UL144 binds BTLA, but not LIGHT, and inhibits T cell proliferation, selectively mimicking the inhibitory cosignaling function of HVEM. The demonstration that distinct herpesviruses target the HVEM-BTLA cosignaling pathway suggests the importance of this pathway in regulating T cell activation during host defenses.

Original languageEnglish
Pages (from-to)13218-13223
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number37
DOIs
StatePublished - Sep 13 2005

Keywords

  • Costimulation
  • Cytokines
  • Immune evasion
  • Lymphocytes

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