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
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.
J Exp Med. 2017 Jan;214(1):73-89. doi: 10.1084/jem.20160784. Epub 2016 Dec 23.
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.
人类感染爱泼斯坦-巴尔病毒（EBV）是恶性和非恶性B细胞增殖的主要诱因。CD27是T细胞的共刺激分子，遗传性CD27缺陷的特征是对EBV感染高度易感，但其潜在病理机制尚未明确。在本研究中，我们报告了一名因CD70（CD27的配体）缺陷而患有复发性EBV诱导的B细胞增殖（包括霍奇金淋巴瘤）的患者。我们发现，用缺乏CD70的EBV感染的B细胞刺激时，EBV特异性T淋巴细胞不能正常扩增，而B细胞中CD70的表达恢复了扩增，这表明B细胞而非T细胞上的CD70是T细胞有效增殖所必需的。研究发现，B细胞在激活时以及EBV感染期间CD70表达上调。由表达CD70的B细胞触发的T细胞增殖依赖于T细胞上的CD27和CD3。重要的是，用表达CD70的B细胞刺激时，缺乏CD27的T细胞无法增殖。因此，CD70-CD27途径似乎是EBV特异性T细胞免疫的关键组成部分，更广泛地说是B细胞免疫监视的关键组成部分，可能是B细胞恶性肿瘤免疫治疗的靶点。
