CpG-ODN-induced sustained expression of BTLA mediating selective inhibition of human B cells.
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.
INSERM U1068, Centre de Recherche en Cancérologie de Marseille, Marseille, 13009, France.
Marie-Laure
ML
Thibult
Jean-Paul
JP
Rivals
Emilie
E
Mamessier
Julie
J
Gertner-Dardenne
Sonia
S
Pastor
Daniel E
DE
Speiser
Laurent
L
Derré
Daniel
D
Olive
D000276:Adjuvants, Immunologic; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D019556:COS Cells; D019496:Cancer Vaccines; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006801:Humans; D008545:Melanoma / Q000628:therapy; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000276:immunology*; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000276:immunology
D000276:Adjuvants, Immunologic; C482586:BTLA protein, human; C408982:CPG-oligonucleotide; D019496:Cancer Vaccines; D009838:Oligodeoxyribonucleotides; D011971:Receptors, Immunologic; D053240:Receptors, Tumor Necrosis Factor, Member 14; C506028:TNFRSF14 protein, human