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

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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.

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Abbreviations

BTLA:

B- and T-lymphocyte attenuator

CFSE:

Carboxyfluoresceine diacetate succinimidyl ester

HVEM:

Herpes virus entry mediator

PBMC:

Peripheral blood mononuclear cells

s.c.:

Subcutaneous

TLR:

Toll-like receptor

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Acknowledgments

We are obliged to the patients and healthy volunteers for their dedicated collaboration. We thank Dr. Daniel Isnardon and Sébastien Létard for discussion and technical insights. We thank Pfizer and Coley Pharmaceutical Group for pharmaceutical products. This work was supported by grants from Institut National de la Santé et de la Recherche Médicale, the Ludwig Institute for Cancer Research, and the Swiss Cancer League. ML Thibult has been supported by fellowships from Ministère de la Recherche et de l’Enseignement Supérieur and from La Ligue contre le Cancer.

Disclosure of conflict of interest

The authors declare no competing financial interests.

Author information

Authors and Affiliations

  1. INSERM U1068, Centre de Recherche en Cancérologie de Marseille, Marseille, 13009, France

    Marie-Laure Thibult, Emilie Mamessier, Julie Gertner-Dardenne, Sonia Pastor & Daniel Olive

  2. Aix-Marseille Université, UMR 891, 13284, Marseille, France

    Marie-Laure Thibult, Emilie Mamessier, Julie Gertner-Dardenne, Sonia Pastor & Daniel Olive

  3. Institut Paoli Calmettes, IBiSA Cancer Immunomonitoring Platform, 13009, Marseille, France

    Marie-Laure Thibult, Emilie Mamessier, Julie Gertner-Dardenne, Sonia Pastor & Daniel Olive

  4. CNRS, UMR7258, Centre de Recherche en Cancérologie de Marseille, Marseille, 13009, France

    Marie-Laure Thibult, Emilie Mamessier, Julie Gertner-Dardenne, Sonia Pastor & Daniel Olive

  5. Clinical Tumor Biology and Immunotherapy Unit, Ludwig Center of the University of Lausanne, Lausanne, Switzerland

    Daniel E. Speiser

  6. Department of Otolaryngology and Head and Neck Surgery, University Hospital Center and University of Lausanne (CHUV), Lausanne, Switzerland

    Jean-Paul Rivals

  7. Urology Research Unit c/o IMUL, Department of Urology, University Hospital of Lausanne, (CHUV), rue du Bugnon 48, CH-1011, Lausanne, Switzerland

    Laurent Derré

Authors
  1. Marie-Laure Thibult
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  2. Jean-Paul Rivals
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  3. Emilie Mamessier
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  4. Julie Gertner-Dardenne
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  5. Sonia Pastor
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  6. Daniel E. Speiser
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  7. Laurent Derré
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  8. Daniel Olive
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Corresponding author

Correspondence to Laurent Derré.

Additional information

Marie-Laure Thibult, Jean-Paul Rivals, Daniel Olive, and Laurent Derré contributed equally to this work.

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Thibult, ML., Rivals, JP., Mamessier, E. et al. CpG-ODN-induced sustained expression of BTLA mediating selective inhibition of human B cells. J Mol Med 91, 195–205 (2013). https://doi.org/10.1007/s00109-012-0943-7

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  • DOI: https://doi.org/10.1007/s00109-012-0943-7

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