CpG-ODN-induced sustained expression of BTLA mediating selective inhibition of human B cells

J Mol Med (Berl). 2013 Feb;91(2):195-205. doi: 10.1007/s00109-012-0943-7. Epub 2012 Aug 19.

Abstract

BTLA (B- and T-lymphocyte attenuator) is a prominent co-receptor that is structurally and functionally related to CTLA-4 and PD-1. In T cells, BTLA inhibits TCR-mediated activation. In B cells, roles and functions of BTLA are still poorly understood and have never been studied in the context of B cells activated by CpG via TLR9. In this study, we evaluated the expression of BTLA depending on activation and differentiation of human B cell subsets in peripheral blood and lymph nodes. Stimulation with CpG upregulated BTLA, but not its ligand: herpes virus entry mediator (HVEM), on B cells in vitro and sustained its expression in vivo in melanoma patients after vaccination. Upon ligation with HVEM, BTLA inhibited CpG-mediated B cell functions (proliferation, cytokine production, and upregulation of co-stimulatory molecules), which was reversed by blocking BTLA/HVEM interactions. Interestingly, chemokine secretion (IL-8 and MIP1β) was not affected by BTLA/HVEM ligation, suggesting that BTLA-mediated inhibition is selective for some but not all B cell functions. We conclude that BTLA is an important immune checkpoint for B cells, as similarly known for T cells.

Publication types

  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic
  • Animals
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology*
  • COS Cells
  • Cancer Vaccines
  • Cells, Cultured
  • Chlorocebus aethiops
  • Humans
  • Melanoma / therapy
  • Oligodeoxyribonucleotides / pharmacology*
  • Receptors, Immunologic / immunology*
  • Receptors, Tumor Necrosis Factor, Member 14 / immunology

Substances

  • Adjuvants, Immunologic
  • BTLA protein, human
  • CPG-oligonucleotide
  • Cancer Vaccines
  • Oligodeoxyribonucleotides
  • Receptors, Immunologic
  • Receptors, Tumor Necrosis Factor, Member 14
  • TNFRSF14 protein, human