Inherited CD70 deficiency in humans reveals a critical role for the CD70-CD27 pathway in immunity to Epstein-Barr virus infection

  • J Exp Med. 2017 Jan;214(1):73-89. doi: 10.1084/jem.20160784.
Kazushi Izawa  1 ,  Emmanuel Martin  1 ,  Claire Soudais  1  2 ,  Julie Bruneau  2  3 ,  David Boutboul  1 ,  Rémy Rodriguez  1  2 ,  Christelle Lenoir  1 ,  Andrew D Hislop  4 ,  Caroline Besson  5 ,  Fabien Touzot  2  6 ,  Capucine Picard  7  2  8  9 ,  Isabelle Callebaut  10 ,  Jean-Pierre de Villartay  11  2 ,  Despina Moshous  11  2  9 ,  Alain Fischer  2  9  12  13 ,  Sylvain Latour  14  2
Affiliations
  • 1. Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Institut National de la Santé et de la Recherche Médicale UMR 1163, 75015 Paris, France.
  • 2. University Paris Descartes Sorbonne Paris Cité, Imagine Institut, 75015 Paris, France.
  • 3. Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
  • 4. School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, England, UK.
  • 5. Department of Biological Hematology and Immunology, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, 94270 Le Kremlin-Bicêtre, France.
  • 6. Department of Biotherapy, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
  • 7. Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale UMR 1163, 75015 Paris, France.
  • 8. Centre d'Etude des Déficits Immunitaires, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
  • 9. Department of Pediatric Immunology, Hematology, and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
  • 10. Centre National de la Recherche Scientifique UMR 7590, Sorbonne Universities, University Pierre et Marie Curie-Paris 6-MNHN-IRD-IUC, 75005 Paris, France.
  • 11. Laboratory of Dynamic of Genome and Immune System, Institut National de la Santé et de la Recherche Médicale UMR 1163, 75015 Paris, France.
  • 12. Collège de France, 75005 Paris, France.
  • 13. Institut National de la Santé et de la Recherche Médicale UMR 1163, 75015 Paris, France.
  • 14. Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Institut National de la Santé et de la Recherche Médicale UMR 1163, 75015 Paris, France [email protected].
PMID: 28011863 DOI: 10.1084/jem.20160784
Abstract

Epstein-Barr virus (EBV) Infection in humans is a major trigger of malignant and nonmalignant B cell proliferations. CD27 is a co-stimulatory molecule of T cells, and inherited CD27 deficiency is characterized by high susceptibility to EBV Infection, though the underlying pathological mechanisms have not yet been identified. In this study, we report a patient suffering from recurrent EBV-induced B cell proliferations including Hodgkin's lymphoma because of a deficiency in CD70, the ligand of CD27. We show that EBV-specific T lymphocytes did not expand properly when stimulated with CD70-deficient EBV-infected B cells, whereas expression of CD70 in B cells restored expansion, indicating that CD70 on B cells but not on T cells is required for efficient proliferation of T cells. CD70 was found to be up-regulated on B cells when activated and during EBV Infection. The proliferation of T cells triggered by CD70-expressing B cells was dependent on CD27 and CD3 on T cells. Importantly, CD27-deficient T cells failed to proliferate when stimulated with CD70-expressing B cells. Thus, the CD70-CD27 pathway appears to be a crucial component of EBV-specific T cell immunity and more generally for the immune surveillance of B cells and may be a target for immunotherapy of B cell malignancies.

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