A coreceptor interaction between the CD28 and TNF receptor family members B and T lymphocyte attenuator and herpesvirus entry mediator

Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1116-21. doi: 10.1073/pnas.0409071102. Epub 2005 Jan 12.

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.

MeSH terms

  • Animals
  • Humans
  • Lymphocyte Activation
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • 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*
  • T-Lymphocytes / immunology
  • Tumor Necrosis Factor Ligand Superfamily Member 14
  • Tumor Necrosis Factor-alpha / metabolism
  • Viral Envelope Proteins / metabolism

Substances

  • BTLA protein, human
  • Membrane Proteins
  • Receptors, Immunologic
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Member 14
  • Receptors, Virus
  • TNFRSF14 protein, human
  • TNFSF14 protein, human
  • Tnfrsf14 protein, mouse
  • Tnfsf14 protein, mouse
  • Tumor Necrosis Factor Ligand Superfamily Member 14
  • Tumor Necrosis Factor-alpha
  • Viral Envelope Proteins
  • glycoprotein D, Human herpesvirus 1