Lactate Dehydrogenase-Elevating Virus Induces Systemic Lymphocyte Activation via TLR7-Dependent IFNα Responses by Plasmacytoid Dendritic Cells
Lactate Dehydrogenase-Elevating Virus Induces Systemic Lymphocyte Activation via TLR7-Dependent IFNα Responses by Plasmacytoid Dendritic Cells
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DOI：
10.1371/journal.pone.0006105
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发表时间：
2009-07-01
期刊：
影响因子：
3.7
通讯作者：
Hasenkrug, Kim J.
中科院分区：
文献类型：
--
作者：
Ammann, Christoph G.;Messer, Ronald J.;Hasenkrug, Kim J.
背景：乳酸脱氢酶升高病毒（LDV）是小鼠的一种自然感染因子。像其他几种病毒一样，LDV引起淋巴组织和血液中B细胞和T细胞的广泛和非常快速但短暂的激活。这种激活的机制尚未完全描述，并且是当前研究的焦点。主要发现：早期淋巴细胞激活的已知诱导剂是IFN α，这是一种由LDV感染强烈诱导的细胞因子。感染小鼠血浆中IFN α的中和作用可消除其体外激活淋巴细胞的能力。由于体内病毒诱导的IFN α的主要来源通常是浆细胞样树突状细胞（pDC），我们在LDV感染之前耗尽这些细胞并测试淋巴细胞活化。pDC在体内的消耗根除了LDV诱导的IFN α应答和淋巴细胞活化。单链RNA病毒如LDV的pDC中的主要受体是toll样受体7（TLR 7）模式识别受体。TLR 7基因敲除小鼠的感染揭示了IFN α应答和淋巴细胞活化都依赖于体内TLR 7信号传导。有趣的是，病毒水平在TLR 7基因敲除小鼠和pDC-耗尽的小鼠是无法区分的控制表明，LDV是在很大程度上抵抗全身IFN α response.Conclusion：结果表明，LDV诱导的淋巴细胞活化是由于识别LDV核酸的TLR 7模式识别受体在pDC的，响应与淋巴细胞诱导IFN α的反应。
Background: Lactate dehydrogenase-elevating virus (LDV) is a natural infectious agent of mice. Like several other viruses, LDV causes widespread and very rapid but transient activation of both B cells and T cells in lymphoid tissues and the blood. The mechanism of this activation has not been fully described and is the focus of the current studies.Principal Findings: A known inducer of early lymphocyte activation is IFN alpha, a cytokine strongly induced by LDV infection. Neutralization of IFN alpha in the plasma from infected mice ablated its ability to activate lymphocytes in vitro. Since the primary source of virus-induced IFN alpha in vivo is often plasmacytoid dendritic cells (pDC's), we depleted these cells prior to LDV infection and tested for lymphocyte activation. Depletion of pDC's in vivo eradicated both the LDV-induced IFN alpha response and lymphocyte activation. A primary receptor in pDC's for single stranded RNA viruses such as LDV is the toll-like receptor 7 (TLR7) pattern recognition receptor. Infection of TLR7-knockout mice revealed that both the IFN alpha response and lymphocyte activation were dependent on TLR7 signaling in vivo. Interestingly, virus levels in both TLR7 knockout mice and pDC-depleted mice were indistinguishable from controls indicating that LDV is largely resistant to the systemic IFN alpha response.Conclusion: Results indicate that LDV-induced activation of lymphocytes is due to recognition of LDV nucleic acid by TLR7 pattern recognition receptors in pDC's that respond with a lymphocyte-inducing IFN alpha response.