title: A coreceptor interaction between the CD28 and TNF receptor family members B and T lymphocyte attenuator and herpesvirus entry mediator.
abstract: Immune cell cosignaling receptors are important modulators of immune cell function. For T cells, cosignaling receptors supply necessary secondary signals supporting activation or attenuation after engagement of antigen-presenting cells. The primary cosignaling receptors belong to either the Ig (CD28-like) or TNF receptor (TNFR) superfamilies. The CD28 family is comprised of coinhibitory and costimulatory receptors. The three coinhibitory receptors are cytotoxic T lymphocyte antigen 4, programmed death-1, and B and T lymphocyte attenuator (BTLA). Although cytotoxic T lymphocyte antigen 4 and programmed death-1 interact with B7-Ig family counter receptors, the ligand for BTLA is less clear. From a protein-protein interaction screen, we identified the TNFR family member herpesvirus entry mediator (HVEM) as a counter receptor for BTLA. Here we show that HVEM binds BTLA with high affinity and can form a ternary complex with its known ligands homologous to lymphotoxin, showing inducible expression, and competing with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT) or lymphotoxin alpha and BTLA. In addition, binding of HVEM to BTLA attenuates T cell activation, identifying HVEM/BTLA as a coinhibitory receptor pair. This study is a demonstration of a direct interaction between the primary T cell cosignaling receptors of the CD28 and TNFR families.
authors.affiliation: Departments of Protein Chemistry and Immunology, Genentech, Inc., South San Francisco, CA 94080-4918, USA.
authors.forename: Lino C
authors.initials: LC
authors.lastname: Gonzalez
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Loyet
authors.forename: Jill
authors.initials: J
authors.lastname: Calemine-Fenaux
authors.forename: Vandana
authors.initials: V
authors.lastname: Chauhan
authors.forename: Bernd
authors.initials: B
authors.lastname: Wranik
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ouyang
authors.forename: Dan L
authors.initials: DL
authors.lastname: Eaton
mesh_terms: D000818:Animals; D006801:Humans; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011971:Receptors, Immunologic / Q000737:chemistry / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000378:metabolism*; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus / Q000737:chemistry / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000378:metabolism
chemical_list: C482586:BTLA protein, human; 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; C506029:Tnfrsf14 protein, mouse; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; D014759:Viral Envelope Proteins; C039447:glycoprotein D, Human herpesvirus 1