title: Inherited CD70 deficiency in humans reveals a critical role for the CD70-CD27 pathway in immunity to Epstein-Barr virus infection.
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.
authors.affiliation: Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Institut National de la Santé et de la Recherche Médicale UMR 1163, 75015 Paris, France.
authors.forename: Kazushi
authors.identifier: 0000-0003-1080-0936
authors.initials: K
authors.lastname: Izawa
authors.affiliation: Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Institut National de la Santé et de la Recherche Médicale UMR 1163, 75015 Paris, France.
authors.forename: Emmanuel
authors.identifier: 0000-0003-4211-7373
authors.initials: E
authors.lastname: Martin
authors.affiliation: Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Institut National de la Santé et de la Recherche Médicale UMR 1163, 75015 Paris, France.|University Paris Descartes Sorbonne Paris Cité, Imagine Institut, 75015 Paris, France.
authors.forename: Claire
authors.identifier: 0000-0002-4387-6649
authors.initials: C
authors.lastname: Soudais
authors.affiliation: University Paris Descartes Sorbonne Paris Cité, Imagine Institut, 75015 Paris, France.|Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Bruneau
authors.affiliation: Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Institut National de la Santé et de la Recherche Médicale UMR 1163, 75015 Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Boutboul
authors.affiliation: Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Institut National de la Santé et de la Recherche Médicale UMR 1163, 75015 Paris, France.|University Paris Descartes Sorbonne Paris Cité, Imagine Institut, 75015 Paris, France.
authors.forename: Rémy
authors.identifier: 0000-0003-3392-6371
authors.initials: R
authors.lastname: Rodriguez
authors.affiliation: Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Institut National de la Santé et de la Recherche Médicale UMR 1163, 75015 Paris, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Lenoir
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, England, UK.
authors.forename: Andrew D
authors.identifier: 0000-0002-9521-5295
authors.initials: AD
authors.lastname: Hislop
authors.affiliation: Department of Biological Hematology and Immunology, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, 94270 Le Kremlin-Bicêtre, France.
authors.forename: Caroline
authors.identifier: 0000-0003-4364-7173
authors.initials: C
authors.lastname: Besson
authors.affiliation: University Paris Descartes Sorbonne Paris Cité, Imagine Institut, 75015 Paris, France.|Department of Biotherapy, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Touzot
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale UMR 1163, 75015 Paris, France.|University Paris Descartes Sorbonne Paris Cité, Imagine Institut, 75015 Paris, France.|Centre d'Etude des Déficits Immunitaires, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.|Department of Pediatric Immunology, Hematology, and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Centre National de la Recherche Scientifique UMR 7590, Sorbonne Universities, University Pierre et Marie Curie-Paris 6-MNHN-IRD-IUC, 75005 Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Callebaut
authors.affiliation: Laboratory of Dynamic of Genome and Immune System, Institut National de la Santé et de la Recherche Médicale UMR 1163, 75015 Paris, France.|University Paris Descartes Sorbonne Paris Cité, Imagine Institut, 75015 Paris, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: de Villartay
authors.affiliation: Laboratory of Dynamic of Genome and Immune System, Institut National de la Santé et de la Recherche Médicale UMR 1163, 75015 Paris, France.|University Paris Descartes Sorbonne Paris Cité, Imagine Institut, 75015 Paris, France.|Department of Pediatric Immunology, Hematology, and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
authors.forename: Despina
authors.identifier: 0000-0001-6719-3693
authors.initials: D
authors.lastname: Moshous
authors.affiliation: University Paris Descartes Sorbonne Paris Cité, Imagine Institut, 75015 Paris, France.|Department of Pediatric Immunology, Hematology, and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.|Collège de France, 75005 Paris, France.|Institut National de la Santé et de la Recherche Médicale UMR 1163, 75015 Paris, France.
authors.forename: Alain
authors.identifier: 0000-0003-4025-5983
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Institut National de la Santé et de la Recherche Médicale UMR 1163, 75015 Paris, France sylvain.latour@inserm.fr.|University Paris Descartes Sorbonne Paris Cité, Imagine Institut, 75015 Paris, France.
authors.forename: Sylvain
authors.identifier: 0000-0001-8238-4391
authors.initials: S
authors.lastname: Latour
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology; D053282:CD27 Ligand / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002648:Child; D018389:Codon, Nonsense; D020031:Epstein-Barr Virus Infections / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000502:physiology*
chemical_list: D053282:CD27 Ligand; C505771:CD70 protein, human; D018389:Codon, Nonsense; D011948:Receptors, Antigen, T-Cell; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7