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

Cheung, T. C., Humphreys, Ian R. ORCID: https://orcid.org/0000-0002-9512-5337, Potter, K. G., Norris, P. S., Shumway, H. M., Tran, B. R., Patterson, G., Jean-Jacques, R., Yoon, M., Spear, P. G., Murphy, K. M., Lurain, N. S., Benedict, C. A. and Ware, C. F. 2005. Evolutionarily divergent herpesviruses modulate T cell activation by targeting the herpesvirus entry mediator cosignaling pathway. Proceedings of the National Academy of Sciences 102 (47) , pp. 13218-13223. 10.1073/pnas.0506172102

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	Q Science > QR Microbiology > QR180 Immunology R Medicine > R Medicine (General)
Uncontrolled Keywords:	cytokines; immune evasion; T lymphocytes; costimulation Base Sequence Binding Sites Binding, Competitive Cytomegalovirus/immunology Cytomegalovirus/physiology Herpesviridae/immunology* Herpesviridae/physiology Herpesvirus 1, Human/immunology Herpesvirus 1, Human/physiology Humans Lymphocyte Activation/immunology* Membrane Glycoproteins/metabolism Membrane Proteins/metabolism Molecular Sequence Data Phylogeny Receptors, Immunologic/metabolism* Receptors, Tumor Necrosis Factor/immunology Receptors, Tumor Necrosis Factor/metabolism Receptors, Tumor Necrosis Factor/physiology* Receptors, Tumor Necrosis Factor, Member 14 Receptors, Virus/immunology Receptors, Virus/metabolism Receptors, Virus/physiology* Signal Transduction T-Lymphocytes/immunology T-Lymphocytes/virology* Tumor Necrosis Factor Ligand Superfamily Member 14 Tumor Necrosis Factor-alpha/metabolism Viral Envelope Proteins/metabolism Viral Proteins/metabolism
Publisher:	National Academy of Sciences
ISSN:	1091-6490
Last Modified:	17 Oct 2022 08:27
URI:	https://orca.cardiff.ac.uk/id/eprint/207

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