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The effects of toll-like receptor ligand-activated dendritic cells on human CD4+ T cell responses.

机译：Toll样受体配体激活的树突状细胞对人CD4 + T细胞反应的影响。

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摘要

Dendritic cells (DCs) play an important role as a link between innate and adaptive immunity through their abilities to detect pathogens and to prime naive T cells (signal 1 and 2). They not only activate naive T cells, but also direct differentiation of CD4+ T cells to induce appropriate immune responses against pathogens via cytokine production (signal 3). In this study, human monocyte-derived dendritic cells (moDCs) as a model for myeloid DCs were activated in vitro with an array of Toll-like receptor (TLR) ligands derived from or mimicking various pathogens, to determine their cytokine profiles, as well as the ability of these differentially TLR ligand-activated DCs to induce differentiation of naive CD4+ T cells. moDCs from certain donors activated with a viral TLR ligand, poly I:C (TLR3 ligand), produced interleukin (IL)12p70, whereas moDCs from the other DC donors produced undetectable amounts of IL12p70. Thus, the DC donors were divided into two groups for further investigation: low responders (LR) and high responders (HR). Bacterial TLR ligands failed to induce production of detectable levels of IL12p70 from both LR and HR donor moDCs. Overall, poly I:C-activated moDCs heavily skewed Th1 differentiation in human allogeneic naive CD4+ T cells relative to that induced by moDCs activated with bacterial TLR ligands (LPS: TLR4 ligand and flagellin: TLR5 ligand) or another viral TLR ligand (ssRNA40: TLR7/8 ligand). Poly I:C-activated HR moDCs induced more heavily skewed Th1 differentiation than that of poly I:C-activated LR moDCs. Conversely, the bacterial TLR ligandactivated moDCs induced relatively balanced Th1/Th2 responses. Neutralization of IL12p70 in these DC/T cell cocultures demonstrated that IL12p70 plays a predominant role in Th1 differentiation in these cocultures.;We also observed that moDCs activated with two of bacterial TLR ligands tested, LPS and Pam3CSK4 (TLR1/2 ligand), induced their production of IL6 and IL1beta. These moDCs also induced the highest levels of Th17 differentiation in the DC/T cell coculture compared to those using moDCs activated with poly I:C, flagellin and ssRNA40. Neutralization of IL1beta, IL6 or TGFbeta revealed that both TGFbeta (presumably T cell-derived) and DC-derived ILbeta are absolutely, but IL6 is only partially, required for Th17 differentiation in the cocultures. On the other hand, only TGFbeta and IL1beta, but not IL6, were required for Th17 differentiation in an APC-free system. This was due to the addition of large amounts of IL1beta in the APC-free system, in which case IL6 was dispensable. This differs from the coculture system, in which only small amounts of IL1beta were produced by the activated DCs. Taken together, bacterial TLR ligand (Pam3CSK4, LPS and MPL-A, flagellin: TLR1/2, 4, 5 ligands, respectively)- as well as a viral TLR ligand (ssRNA40: a TLR7/8 ligand)-activated moDCs induced relatively more balanced Th1/Th2/Th17 CD4+ T cell differentiation whereas another viral TLR ligand (poly I:C: a TLR3 ligand) induced more heavily skewed Th1 differentiation. These results provide a framework for the use of these TLR ligands in tailoring T cell responses in vaccines and other immunotherapeutic approaches.
机译：树突状细胞（DC）通过其检测病原体和引发幼稚T细胞（信号1和2）的能力，在先天免疫和适应性免疫之间起着重要的作用。它们不仅激活幼稚的T细胞，还指导CD4 + T细胞的分化，从而通过细胞因子的产生诱导针对病原体的适当免疫反应（信号3）。在这项研究中，人类单核细胞来源的树突状细胞（moDCs）作为骨髓DC的模型在体外被一系列源自或模仿各种病原体的Toll样受体（TLR）配体激活，以确定它们的细胞因子谱。这些差异性TLR配体激活的DC诱导幼稚CD4 + T细胞分化的能力。来自某些被病毒TLR配体poly I：C（TLR3配体）激活的供体的moDC产生白介素（IL）12p70，而来自其他DC供体的moDC产生不可检测量的IL12p70。因此，DC捐助者分为两组进行进一步调查：低响应者（LR）和高响应者（HR）。细菌TLR配体无法诱导LR和HR供体moDC产生可检测水平的IL12p70。总体而言，与由细菌TLR配体（LPS：TLR4配体和鞭毛蛋白：TLR5配体）或另一种病毒TLR配体（ssRNA40： TLR7 / 8配体）。聚I：C激活的HR moDC比聚I：C激活的LR moDC诱导的Th1分化更严重。相反，细菌TLR配体激活的moDC诱导了相对平衡的Th1 / Th2反应。在这些DC / T细胞共培养物中对IL12p70的中和表明，IL12p70在这些共培养物中的Th1分化中起主要作用。;我们还观察到被两个细菌TLR配体LPS和Pam3CSK4（TLR1 / 2配体）激活的moDC被诱导。它们产生IL6和IL1beta。与使用由poly I：C，鞭毛蛋白和ssRNA40激活的moDC相比，这些moDC在DC / T细胞共培养中还诱导了最高水平的Th17分化。 IL1beta，IL6或TGFbeta的中和显示，TGFbeta（大概是T细胞衍生的）和DC衍生的ILbeta都是绝对的，但共培养中Th17分化只需要IL6。另一方面，在无APC的系统中，Th17分化仅需要TGFbeta和IL1beta，而不需要IL6。这是由于在无APC的系统中添加了大量IL1beta，在这种情况下，IL6是可有可无的。这不同于共培养系统，在共培养系统中，活化的DC仅产生少量的IL1beta。细菌TLR配体（Pam3CSK4，LPS和MPL-A，鞭毛蛋白：分别为TLR1 / 2、4、5个配体）和病毒TLR配体（ssRNA40：TLR7 / 8配体）激活的moDC合起来相对诱导更平衡的Th1 / Th2 / Th17 CD4 + T细胞分化，而另一种病毒TLR配体（poly I：C：TLR3配体）则导致Th1分化更严重。这些结果为使用这些TLR配体在疫苗和其他免疫疗法中调整T细胞应答提供了框架。

著录项

  • 作者

    Benwell, Risa Kitawaki.;

  • 作者单位

    University of Missouri - Columbia.;

  • 授予单位 University of Missouri - Columbia.;
  • 学科 Biology Cell.;Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 173 p.
  • 总页数 173
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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