Impaired innate immunity in Tlr4(-/-) mice but preserved CD8+ T cell responses against Trypanosoma cruzi in Tlr4-, Tlr2-, Tlr9- or Myd88-deficient mice.
Impaired innate immunity in Tlr4(-/-) mice but preserved CD8+ T cell responses against Trypanosoma cruzi in Tlr4-, Tlr2-, Tlr9- or Myd88-deficient mice.
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DOI：
10.1371/journal.ppat.1000870
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发表时间：
2010-04-29
期刊：
影响因子：
6.7
通讯作者：
Bellio M
中科院分区：
文献类型：
--
作者：
Oliveira AC;de Alencar BC;Tzelepis F;Klezewsky W;da Silva RN;Neves FS;Cavalcanti GS;Boscardin S;Nunes MP;Santiago MF;Nóbrega A;Rodrigues MM;Bellio M
克氏锥虫感染的小鼠模型提供了令人信服的证据，表明宿主对细胞内原生动物的抵抗力的发展关键取决于 Toll 样受体 (TLR) 家族成员通过 MyD88 接头分子的激活。然而，迄今为止，TLR/MyD88 信号通路也控制免疫保护性 CD8+ T 细胞介导的效应功能的诱导的可能性尚未得到研究。我们通过测量 H-2Kb 限制性免疫显性肽特异性的 IFN-γ 分泌 CD8+ T 细胞的频率以及 TLR2、TLR4、TLR9 或 MyD88 信号通路缺陷的受感染动物体内 Ag 特异性细胞毒性反应来解决这个问题。引人注目的是，我们发现克氏锥虫感染的 Tlr2−/−、Tlr4−/−、Tlr9−/− 或 Myd88−/− 小鼠产生了特异性细胞毒性反应，并且分泌 IFN-γ 的 CD8+ T 细胞的水平与 WT 小鼠相当，尽管感染 Myd88−/− 中 IFN-γ+CD4+ 细胞的频率减少了。 老鼠。我们还使用 TLR4 缺陷小鼠在 C57BL 遗传背景（B6 和 B10）上分析了 TLR4 驱动的针对克氏锥虫的免疫反应的效率。我们的研究表明，TLR4 信号传导是受感染动物脾脏中 IFN-γ、TNF-α 和一氧化氮 (NO) 最佳产生所必需的，因此，Tlr4−/− 小鼠表现出较高的寄生虫血症水平。总的来说，我们的结果表明，TLR4 以及之前显示的 TLR2、TLR9 和 MyD88 有助于先天免疫反应，从而有助于感染急性期的抵抗力，尽管这些途径中的每一个对于产生针对克氏锥虫的 I 类限制性反应并不是单独必需的。先天性和获得性免疫反应在感染克氏锥虫（恰加斯病的病原体）时被触发，对于宿主的生存至关重要。寄生虫负担通常在适应性反应开始发挥作用时得到控制。然而，克氏锥虫设法在细胞内生存并建立慢性感染，导致大约三分之一的感染者患上心肌病。最近，Toll 样受体 (TLR) 已被证明能够识别克氏锥虫分子，而缺乏 MyD88（大多数 TLR 的关键接头）的小鼠极易受到感染。尽管已知 TLR 将先天反应和适应性反应联系起来，但它们在克氏锥虫感染期间由 CD8+ T 细胞介导的关键效应机制建立中的作用尚未确定。我们分析了 TLR2、TLR4、TLR9 或 MyD88 缺陷小鼠在感染过程中体内 IFN-γ 的诱导和细胞毒活性，并发现与 WT 小鼠相比完整的反应。我们还证明，TLR4 是炎性细胞因子和一氧化氮最佳产生所必需的，从而更好地控制寄生虫血症水平。了解 TLR 激活如何导致对感染的抵抗力可能有助于制定更好的策略来改善针对这种病原体的免疫反应。
The murine model of T. cruzi infection has provided compelling evidence that development of host resistance against intracellular protozoans critically depends on the activation of members of the Toll-like receptor (TLR) family via the MyD88 adaptor molecule. However, the possibility that TLR/MyD88 signaling pathways also control the induction of immunoprotective CD8+ T cell-mediated effector functions has not been investigated to date. We addressed this question by measuring the frequencies of IFN-γ secreting CD8+ T cells specific for H-2Kb-restricted immunodominant peptides as well as the in vivo Ag-specific cytotoxic response in infected animals that are deficient either in TLR2, TLR4, TLR9 or MyD88 signaling pathways. Strikingly, we found that T. cruzi-infected Tlr2−/−, Tlr4−/−, Tlr9−/ − or Myd88−/− mice generated both specific cytotoxic responses and IFN-γ secreting CD8+ T cells at levels comparable to WT mice, although the frequency of IFN-γ+CD4+ cells was diminished in infected Myd88−/− mice. We also analyzed the efficiency of TLR4-driven immune responses against T. cruzi using TLR4-deficient mice on the C57BL genetic background (B6 and B10). Our studies demonstrated that TLR4 signaling is required for optimal production of IFN-γ, TNF-α and nitric oxide (NO) in the spleen of infected animals and, as a consequence, Tlr4−/− mice display higher parasitemia levels. Collectively, our results indicate that TLR4, as well as previously shown for TLR2, TLR9 and MyD88, contributes to the innate immune response and, consequently, resistance in the acute phase of infection, although each of these pathways is not individually essential for the generation of class I-restricted responses against T. cruzi. Innate and acquired immune responses are triggered during infection with T. cruzi, the etiologic agent of Chagas' disease, and are critical for host survival. Parasite burden is usually controlled by the time the adaptive response becomes operational. Nevertheless, T. cruzi manages to subsist within intracellular niches and establishes a chronic infection, leading to the development of cardiomyopathy in approximately one-third of infected individuals. Recently, Toll-like receptors (TLRs) have been shown to recognize T. cruzi molecules and mice lacking MyD88, the key adaptor for most TLRs, are extremely susceptible to infection. Although TLRs are known to link innate and adaptive responses, their role in the establishment of crucial effector mechanisms mediated by CD8+ T cells during T. cruzi infection has not yet been determined. We analyzed the induction of IFN-γ and cytotoxic activity in vivo in TLR2-, TLR4-, TLR9- or MyD88-deficient mice during infection, and found intact responses compared to WT mice. We also demonstrated that TLR4 is required for optimal production of inflammatory cytokines and nitric oxide and, consequently, for a better control of parasitemia levels. Understanding how TLR activation leads to resistance to infection might contribute to the development of better strategies to improve immune responses against this pathogen.
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影响因子：
56.9
作者：
Blander, JM;Medzhitov, R
通讯作者：
Medzhitov, R
影响因子：
2.9
作者：
GREEN, LC;WAGNER, DA;TANNENBAUM, SR
通讯作者：
TANNENBAUM, SR
影响因子：
5.5
作者：
de Alencar, Bruna C. G.;Araujo, Adriano F. S.;Rodrigues, Mauricio M.
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Rodrigues, Mauricio M.
影响因子：
4.4
作者：
Heer, Alex K.;Shamshiev, Abdijapar;Marsland, Benjamin J.
通讯作者：
Marsland, Benjamin J.
影响因子：
6.7
作者：
Browne, Edward P.;Littman, Dan R.
通讯作者：
Littman, Dan R.