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首页> 外文学位 >Immunomodulatory signaling by HCV core protein through the complement receptor,gC1qR, on antigen-presenting cells.
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Immunomodulatory signaling by HCV core protein through the complement receptor,gC1qR, on antigen-presenting cells.

机译：HCV核心蛋白通过补体受体gC1qR对抗原呈递细胞进行免疫调节信号转导。

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摘要

Innate immunity is activated very rapidly following microbial insult and is critical to the development of adaptive immune responses. Dendritic cells (DCs) in particular are crucial for the activation of pathogen-specific T lymphocytes. Specifically, TLR ligand-induced production of IL-12 by DCs is important for T cell-mediated IFN-gamma production and antiviral activity.; The central role of IL-12 in both the resolution of infection and the induction of autoimmune disease implies that microbe- and host-mediated mechanisms must exist to regulate production of IL-12. In fact, the putative C1q receptor, gC1qR, has been implicated in the specific suppression of TLR-induced IL-12 production by DCs. This receptor interacts with a number of bacterially- and virally-encoded proteins, including hepatitis C virus (HCV) core. Given the high rate of persistent infection with HCV, due in part to defects in T cell-mediated IFN-gamma production, the association of core protein with gC1gR is likely to play a role in dysregulation of host immunity and establishment of chronic infection.; To examine the impact of HCV core/gC1qR interaction-induced signaling on DC activation and T cell stimulatory capacity, we first generated monoclonal antibodies specific for gC1gR. Ligation of gC1gR on human monocytes and DCs results in a potent, albeit specific, suppression of TLR-stimulated production of IL-12. Of interest, TLR-induced expression of co-stimulatory receptors and additional cytokines was completely normal. Importantly, suppression of IL-12 secretion by anti-gC1gR antibody was mediated through activation of the P13K pathway. Following treatment with anti-gC1qR antibody or HCV core protein, DCs displayed a reduced ability to induce IFN-gamma production and TH1 differentiation of CD4+ T cells. Moreover, the phenotype of these T cells was skewed in favor of increased TH2 cytokine secretion (e.g. IL-4). The inhibition of TH1 cytokine induction by anti-gC1gR antibody- or core-treated DCs was completely abrogated following restoration of IL-12 levels in the DC/T cell co-culture. These results indicate that gC1gR plays a potentially crucial role in the negative regulation of IL-12 production and subsequent differentiation of TH1 immune responses. Therefore, gC1qR-dependent immune regulation may be subverted during the establishment and maintenance of chronic HCV infection.
机译：先天免疫在受到微生物侵害后很快被激活，这对适应性免疫反应的发展至关重要。树突状细胞（DC）特别对于病原体特异性T淋巴细胞的激活至关重要。特别地，DCs的TLR配体诱导的IL-12的产生对于T细胞介导的IFN-γ产生和抗病毒活性是重要的。 IL-12在感染的消退和自身免疫疾病的诱导中的核心作用意味着必须存在微生物和宿主介导的机制来调节IL-12的产生。实际上，推定的C1q受体gC1qR与DC抑制TLR诱导的IL-12产生有关。该受体与许多细菌和病毒编码的蛋白质相互作用，包括丙型肝炎病毒（HCV）核心。鉴于HCV持续感染的高发生率，部分是由于T细胞介导的IFN-γ产生缺陷，核心蛋白与gC1gR的缔合可能在宿主免疫失调和慢性感染的建立中起作用。为了检查HCV核心/ gC1qR相互作用诱导的信号传导对DC激活和T细胞刺激能力的影响，我们首先生成了对gC1gR特异的单克隆抗体。 gC1gR在人单核细胞和DC上的连接可有效抑制TLR刺激的IL-12产生，尽管是特异性的。有趣的是，TLR诱导的共刺激受体和其他细胞因子的表达是完全正常的。重要的是，抗gC1gR抗体抑制IL-12分泌是通过激活P13K途径介导的。用抗gC1qR抗体或HCV核心蛋白处理后，DC诱导IFN-γ产生和CD4 + T细胞TH1分化的能力降低。此外，这些T细胞的表型偏向有利于TH2细胞因子分泌的增加（例如IL-4）。在DC / T细胞共培养物中恢复IL-12水平后，完全消除了抗gC1gR抗体或核心处理的DC对TH1细胞因子诱导的抑制作用。这些结果表明，gC1gR在IL-12产生的负调控和TH1免疫应答的后续分化中起着潜在的关键作用。因此，在慢性HCV感染的建立和维持过程中，可能会破坏gC1qR依赖性免疫调节。

著录项

  • 作者

    Waggoner, Stephen Noel.;

  • 作者单位

    University of Virginia.;

  • 授予单位 University of Virginia.;
  • 学科 Biology Virology.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 229 p.
  • 总页数 229
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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