Evolutionarily divergent herpesviruses modulate T cell activation by targeting the herpesvirus entry mediator cosignaling pathway.
The herpesvirus entry mediator (HVEM), a member of the TNF receptor (TNFR) superfamily, can act as a molecular switch that modulates T cell activation by propagating positive signals from the TNF-related ligand LIGHT (TNFR superfamily 14), or inhibitory signals through the Ig superfamily 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.
Cheung
Timothy C
TC
Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA.
Humphreys
Ian R
IR
Potter
Karen G
KG
Norris
Paula S
PS
Shumway
Heather M
HM
Tran
Bonnie R
BR
Patterson
Ginelle
G
Jean-Jacques
Rochelle
R
Yoon
Miri
M
Spear
Patricia G
PG
Murphy
Kenneth M
KM
Lurain
Nell S
NS
Benedict
Chris A
CA
Ware
Carl F
CF
D001483:Base Sequence; D001665:Binding Sites; D001667:Binding, Competitive; D003587:Cytomegalovirus / Q000276:immunology / Q000502:physiology; D006564:Herpesviridae / Q000276:immunology* / Q000502:physiology; D018259:Herpesvirus 1, Human / Q000276:immunology / Q000502:physiology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D010802:Phylogeny; D011971:Receptors, Immunologic / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology*; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism
C482586:BTLA protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D018124:Receptors, Tumor Necrosis Factor; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus; C506028:TNFRSF14 protein, human; C505914:TNFSF14 protein, human; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; C119624:UL144 ORF protein, Human herpesvirus 5; D014759:Viral Envelope Proteins; D014764:Viral Proteins