A Coreceptor Interaction between the CD28 and TNF Receptor Family Members B and T Lymphocyte Attenuator and Herpesvirus Entry Mediator

• Published in: Proceedings of the National Academy of Sciences - PNAS 2005-01, Vol.102 (4), p.1116-1121
• Main Authors: Gonzalez, Lino C., Loyet, Kelly M., Calemine-Fenaux, Jill, Chauhan, Vandana, Wranik, Bernd, Ouyang, Wenjun, Eaton, Dan L., Scheller, Richard H.
• Format: Article
• Language: English
• Subjects: 3T3 cells; Animals; Antigens; Biological Sciences; Cell lines; Cells; Family members; Herpes simplex virus; Herpes viruses; Herpesviridae; Herpesvirus; Humans; Immunology; Ligands; Lymphocyte Activation; Membrane Proteins - metabolism; Mice; Mice, Inbred BALB C; Receptors; Receptors, Immunologic - chemistry; Receptors, Immunologic - metabolism; Receptors, Tumor Necrosis Factor - chemistry; Receptors, Tumor Necrosis Factor - metabolism; Receptors, Tumor Necrosis Factor, Member 14; Receptors, Virus - chemistry; Receptors, Virus - metabolism; Signal transduction; T cell antigen receptors; T cell receptors; T lymphocytes; T-Lymphocytes - immunology; Tumor Necrosis Factor Ligand Superfamily Member 14; Tumor Necrosis Factor-alpha - metabolism; Viral Envelope Proteins - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0409071102

Immune cell consignaling 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 constimulatory 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 α 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.