title: T cell intrinsic heterodimeric complexes between HVEM and BTLA determine receptivity to the surrounding microenvironment.
abstract: The inhibitory cosignaling pathway formed between the TNF receptor herpesvirus entry mediator (HVEM, TNFRSF14) and the Ig superfamily members, B and T lymphocyte attenuator (BTLA) and CD160, limits the activation of T cells. However, BTLA and CD160 can also serve as activating ligands for HVEM when presented in trans by adjacent cells, thus forming a bidirectional signaling pathway. BTLA and CD160 can directly activate the HVEM-dependent NF-kappaB RelA transcriptional complex raising the question of how NF-kappaB activation is repressed in naive T cells. In this study, we show BTLA interacts with HVEM in cis, forming a heterodimeric complex in naive T cells that inhibits HVEM-dependent NF-kappaB activation. The cis-interaction between HVEM and BTLA is the predominant form expressed on the surface of naive human and mouse T cells. The BTLA ectodomain acts as a competitive inhibitor blocking BTLA and CD160 from binding in trans to HVEM and initiating NF-kappaB activation. The TNF-related ligand, LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes, or TNFSF14) binds HVEM in the cis-complex, but NF-kappaB activation was attenuated, suggesting BTLA prevents oligomerization of HVEM in the cis-complex. Genetic deletion of BTLA or pharmacologic disruption of the HVEM-BTLA cis-complex in T cells promoted HVEM activation in trans. Interestingly, herpes simplex virus envelope glycoprotein D formed a cis-complex with HVEM, yet surprisingly, promoted the activation NF-kappaB RelA. We suggest that the HVEM-BTLA cis-complex competitively inhibits HVEM activation by ligands expressed in the surrounding microenvironment, thus helping maintain T cells in the naive state.
authors.affiliation: Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Cheung
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Oborne
authors.forename: Marcos W
authors.initials: MW
authors.lastname: Steinberg
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Macauley
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukuyama
authors.forename: Hideki
authors.initials: H
authors.lastname: Sanjo
authors.forename: Claire
authors.initials: C
authors.lastname: D'Souza
authors.forename: Paula S
authors.initials: PS
authors.lastname: Norris
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfeffer
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Murphy
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kronenberg
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Spear
authors.forename: Carl F
authors.initials: CF
authors.lastname: Ware
mesh_terms: D000818:Animals; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism
chemical_list: C482586:BTLA protein, human; D011971:Receptors, Immunologic; D053240:Receptors, Tumor Necrosis Factor, Member 14