B Lymphocytes Differentiation and Triggering

B 淋巴细胞分化和触发

• 批准号: 6774432
• 负责人: Brigitte T. Huber
• 金额: $ 45.83万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-04-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6774432
• 关键词: B lymphocyte; Burkitt' s lymphoma; CD antigens; Epstein Barr virus; Retroviridae; T cell receptor; antigen presentation; biological signal transduction; cell differentiation; clinical research; complement receptor; gene expression; genetic mapping; genetic screening; genetically modified animals; host organism interaction; human genetic material tag; human subject; interferon alpha; laboratory mouse; microorganism immunology; multiple sclerosis; oncogenic virus; patient oriented research; protein structure function; superantigens; systemic lupus erythematosus; virus diseases; virus genetics

DESCRIPTION (provided by applicant): This competitive renewal application is based on the discovery that the env gene of HERV-K18 (Human Endogenous Retrovirus) encodes a superantigen, which is transcriptionally activated by EBV (Epstein-Barr Virus) and IFN-alpha (type I interferon). The working hypothesis is that the T cell stimulation elicited by the superantigen is not only essential for establishing life-long persistent infection with EBV in healthy individuals, but also plays a crucial role in EBV-associated diseases and malignancies. The following specific aims are proposed to test this model: I) The control of HERV-K18 expression will be defined. The role of CD21 engagement in the initiation of superantigen expression will be analyzed, based on the observation that IFNalpha and EBV infection lead to superantigen expression, both acting through CD21 on resting B cells. Furthermore, the role of EBV LMP-2A in sustained superantigen expression will be evaluated, based on the finding that this EBV latent gene product is sufficient to transactivate HERV-K18 env, leading to superantigen activity. II) HERV-K18 superantigen-reactive cells will be delineated in vivo and in vitro. For this purpose, an HLA.DR/HERV-K18 Env tetramer will be constructed to identify and stimulate superantigen-reactive T cells. The recent discovery of the murine TCR (T cell receptor) Vbeta specificity for the human superantigen will be exploited to define and map the TCR-superantigen interaction site. In addition, the role of CD48 in the superantigen-induced T cell activation will be tested, since EBV upregulates expression of this co-stimulatory molecule. III) The role of the HERV-K18 superantigen in EBV-infection will be determined, because the central dogma of this proposal is that the superantigen activity is required for the successful EBV life-cycle in the human host. In vitro and in vivo EBV-infection/ outgrowth/ persistent latency/lytic cycle/reactivation models will be used to address this aim. IV) The DNA of patients suffering from EBV-associated diseases will be typed for preferential expression of certain HERV-K18 alleles, compared to their respective healthy controls. This aim is based on the observation that the 3 HERV-K18 env alleles defined so far are unequally distributed in the Caucasian population and differ in their superantigen expression level. Collectively, these studies will further the general understanding of how viruses exploit the immune system of their hosts to their own advantage.

描述（申请人提供）：本竞争性续展申请基于HERV-K18（人内源性逆转录病毒）的env基因编码超级抗原的发现，该超级抗原由EBV（EB病毒）和IFN-α转录激活（ I型干扰素）。目前的假设是，超抗原引发的 T 细胞刺激不仅对于健康个体中建立 EBV 终生持续感染至关重要，而且在 EBV 相关疾病和恶性肿瘤中也发挥着至关重要的作用。提出以下具体目标来测试该模型： I) 将定义 HERV-K18 表达的控制。基于 IFNα 和 EBV 感染导致超抗原表达（两者均通过 CD21 对静息 B 细胞起作用）的观察，将分析 CD21 在超抗原表达启动中的作用。此外，还将评估 EBV LMP-2A 在持续超抗原表达中的作用，因为发现该 EBV 潜伏基因产物足以反式激活 HERV-K18 env，从而产生超抗原活性。 II) 将在体内和体外描绘HERV-K18超抗原反应性细胞。为此，将构建 HLA.DR/HERV-K18 Env 四聚体来识别和刺激超抗原反应性 T 细胞。最近发现的鼠 TCR（T 细胞受体）Vbeta 对人类超抗原的特异性将被用来定义和绘制 TCR-超抗原相互作用位点。此外，还将测试 CD48 在超抗原诱导的 T 细胞激活中的作用，因为 EBV 上调这种共刺激分子的表达。 III) HERV-K18 超抗原在 EBV 感染中的作用将被确定，因为该提案的中心法则是超抗原活性是 EBV 在人类宿主中成功生命周期所必需的。体外和体内 EBV 感染/生长/持续潜伏/裂解周期/再激活模型将用于实现这一目标。 IV) 与各自的健康对照相比，将对患有 EBV 相关疾病的患者进行 DNA 分型，以确定某些 HERV-K18 等位基因的优先表达。这一目标基于以下观察结果：迄今为止定义的 3 个 HERV-K18 env 等位基因在高加索人群中分布不均，并且其超抗原表达水平不同。总的来说，这些研究将进一步加深人们对病毒如何利用宿主的免疫系统来获取自身优势的普遍理解。