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

• Published in: The Journal of experimental medicine Vol. 214; no. 1; pp. 73 - 89
• Main Authors: Izawa, Kazushi, Martin, Emmanuel, Soudais, Claire, Bruneau, Julie, Boutboul, David, Rodriguez, Rémy, Lenoir, Christelle, Hislop, Andrew D., Besson, Caroline, Touzot, Fabien, Picard, Capucine, Callebaut, Isabelle, de Villartay, Jean-Pierre, Moshous, Despina, Fischer, Alain, Latour, Sylvain
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 01.01.2017; The Rockefeller University Press
• Subjects: B-Lymphocytes - immunology; CD27 antigen; CD27 Ligand - deficiency; CD27 Ligand - genetics; CD27 Ligand - physiology; CD3 antigen; CD70 antigen; Cell proliferation; Child; Codon, Nonsense; Epstein-Barr virus; Epstein-Barr Virus Infections - immunology; Humans; Immunity; Immunology; Immunosurveillance; Immunotherapy; Infections; Life Sciences; Lymphocyte Activation; Lymphocyte receptors; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Male; Receptors, Antigen, T-Cell - physiology; Signal Transduction - physiology; T-Lymphocytes - immunology; Tumor Necrosis Factor Receptor Superfamily, Member 7 - physiology; Viruses; Immunodeficiency
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20160784

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.