BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination

J Clin Invest. 2010 Jan;120(1):157-67. doi: 10.1172/JCI40070. Epub 2009 Dec 28.


The function of antigen-specific CD8+ T cells, which may protect against both infectious and malignant diseases, can be impaired by ligation of their inhibitory receptors, which include CTL-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1). Recently, B and T lymphocyte attenuator (BTLA) was identified as a novel inhibitory receptor with structural and functional similarities to CTLA-4 and PD-1. BTLA triggering leads to decreased antimicrobial and autoimmune T cell responses in mice, but its functions in humans are largely unknown. Here we have demonstrated that as human viral antigen-specific CD8+ T cells differentiated from naive to effector cells, their surface expression of BTLA was gradually downregulated. In marked contrast, human melanoma tumor antigen-specific effector CD8+ T cells persistently expressed high levels of BTLA in vivo and remained susceptible to functional inhibition by its ligand herpes virus entry mediator (HVEM). Such persistence of BTLA expression was also found in tumor antigen-specific CD8+ T cells from melanoma patients with spontaneous antitumor immune responses and after conventional peptide vaccination. Remarkably, addition of CpG oligodeoxynucleotides to the vaccine formulation led to progressive downregulation of BTLA in vivo and consequent resistance to BTLA-HVEM-mediated inhibition. Thus, BTLA activation inhibits the function of human CD8+ cancer-specific T cells, and appropriate immunotherapy may partially overcome this inhibition.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / physiology
  • Antigens, Neoplasm / immunology*
  • Apoptosis Regulatory Proteins / physiology
  • CD8-Positive T-Lymphocytes / immunology*
  • COS Cells
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Humans
  • Interferon-gamma / biosynthesis
  • Lymphocyte Activation
  • MART-1 Antigen
  • Melanoma / immunology
  • Melanoma / therapy*
  • Neoplasm Proteins / immunology*
  • Oligodeoxyribonucleotides / pharmacology
  • Programmed Cell Death 1 Receptor
  • Receptors, Immunologic / physiology*
  • Receptors, Tumor Necrosis Factor, Member 14 / physiology
  • Vaccination*


  • Antigens, CD
  • Antigens, Neoplasm
  • Apoptosis Regulatory Proteins
  • BTLA protein, human
  • CPG-oligonucleotide
  • MART-1 Antigen
  • MLANA protein, human
  • Mlana protein, mouse
  • Neoplasm Proteins
  • Oligodeoxyribonucleotides
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Immunologic
  • Receptors, Tumor Necrosis Factor, Member 14
  • TNFRSF14 protein, human
  • Interferon-gamma