Induction of IL-12p40 and type 1 immunity by Toxoplasma gondii in the absence of the TLR-MyD88 signaling cascade.
Induction of IL-12p40 and type 1 immunity by Toxoplasma gondii in the absence of the TLR-MyD88 signaling cascade.
复制标题
DOI：
10.1371/journal.ppat.1009970
复制
发表时间：
2021-10
期刊：
影响因子：
6.7
通讯作者：
Denkers EY
中科院分区：
文献类型：
--
作者：
Snyder LM;Doherty CM;Mercer HL;Denkers EY
弓形虫是一种口服获得性病原体，可诱导基于干扰素-γ的强大免疫，提供保护，但这也可能是免疫病理的原因。小鼠的反应在一定程度上是由特征明确的MyD88依赖的信号通路驱动的。在这里，我们专注于诱导不太了解的免疫反应，这些免疫反应不涉及Toll样受体(TLR)/IL-1家族受体适配器分子，特别是当它们发生在肠粘膜中时。利用以MyD88-/-为背景的EYFP-IL-12p40报告小鼠，我们鉴定了经口感染弓形虫后树突状细胞、巨噬细胞和中性粒细胞是MyD88非依赖性IL-12的细胞来源。在没有MyD88的情况下，感染诱导的IL-12较低，但仍明显高于未感染的水平。总体而言，这延续到干扰素-γ反应，虽然普遍下降，但在没有MyD88的情况下仍然非常强劲。在后一组小鼠中，诱导I型免疫需要严格的IL-12。1型和3型先天淋巴样细胞(ILC)、CD_4+T细胞和CD_8+T细胞均构成干扰素-γ池。我们报道，与MyD88+/+小鼠相比，ILC3在感染的MyD88-/-小鼠中扩展，这表明MyD88缺失引发了一种代偿反应。此外，在WT和KO小鼠中，固有层中细菌鞭毛蛋白和弓形虫特异性CD4+T细胞群在感染后扩张。最后，我们证明了MY88非依赖的IL-12和T细胞介导的干扰素-γ的产生需要肠道微生物区系的存在。我们的结果确定了弓形虫诱导的肠道免疫途径不依赖于MyD88，包括髓系细胞产生IL-12、下游的I型免疫以及IL_1、IL_3和T淋巴细胞产生的干扰素-γ。总而言之，我们的数据揭示了一个基本的免疫反应网络，不涉及通过MyD88的信号。弓形虫是一种尖端复合体寄生虫，估计感染全球30%-50%的人类。这种寄生虫通常在大脑和肌肉组织中建立潜伏期，以持续的无症状感染为标志。弓形虫巧妙地在激发强大的抗寄生虫免疫力和在宿主体内坚持之间取得了平衡。虽然小鼠宿主通过MyD88和Toll样受体11/12识别弓形虫Profilin，但人类缺乏这些受体，MyD88缺陷患者仍对弓形虫感染保持抵抗力。鉴于这些观察，重要的是确定MyD88独立的免疫途径。利用口腔感染小鼠模型，我们确定了IL-12和干扰素-γ的细胞来源，这两种细胞因子对宿主对这种微生物病原体的抵抗力至关重要。我们确定了MyD88和肠道微生物区系的存在和不存在对这些反应的影响。我们的数据表明，弓形虫在需要肠道微生物存在的肠道粘膜中触发MyD88独立的先天和获得性免疫。这些途径在不同物种之间可能是保守的，了解它们在啮齿动物中是如何工作的，可能有助于确定人类如何识别和应对弓形虫感染。
Toxoplasma gondii is an orally acquired pathogen that induces strong IFN-γ based immunity conferring protection but that can also be the cause of immunopathology. The response in mice is driven in part by well-characterized MyD88-dependent signaling pathways. Here we focus on induction of less well understood immune responses that do not involve this Toll-like receptor (TLR)/IL-1 family receptor adaptor molecule, in particular as they occur in the intestinal mucosa. Using eYFP-IL-12p40 reporter mice on an MyD88-/- background, we identified dendritic cells, macrophages, and neutrophils as cellular sources of MyD88-independent IL-12 after peroral T. gondii infection. Infection-induced IL-12 was lower in the absence of MyD88, but was still clearly above noninfected levels. Overall, this carried through to the IFN-γ response, which while generally decreased was still remarkably robust in the absence of MyD88. In the latter mice, IL-12 was strictly required to induce type I immunity. Type 1 and type 3 innate lymphoid cells (ILC), CD4+ T cells, and CD8+ T cells each contributed to the IFN-γ pool. We report that ILC3 were expanded in infected MyD88-/- mice relative to their MyD88+/+ counterparts, suggesting a compensatory response triggered by loss of MyD88. Furthermore, bacterial flagellin and Toxoplasma specific CD4+ T cell populations in the lamina propria expanded in response to infection in both WT and KO mice. Finally, we show that My88-independent IL-12 and T cell mediated IFN-γ production require the presence of the intestinal microbiota. Our results identify MyD88-independent intestinal immune pathways induced by T. gondii including myeloid cell derived IL-12 production, downstream type I immunity and IFN-γ production by ILC1, ILC3, and T lymphocytes. Collectively, our data reveal an underlying network of immune responses that do not involve signaling through MyD88. Toxoplasma gondii is an apicomplexan parasite estimated to infect 30–50% of humans worldwide. The parasite normally establishes latency in brain and muscle tissue marked by persistent asymptomatic infection. T. gondii masterfully strikes a balance between eliciting strong, anti-parasite immunity while also persisting in the host. Although the murine host recognizes Toxoplasma profilin via MyD88 and Toll-like receptors 11/12, humans lack these receptors and MyD88 deficient patients retain resistance to T. gondii infection. Given these observations, it is important to identify MyD88 independent pathways of immunity. Using an oral infection mouse model, we identified cellular sources of IL-12 and IFN-γ, two cytokines that are essential for host resistance to this microbial pathogen. We determined how these responses are impacted by the presence and absence of MyD88 and the intestinal microbiota. Our data demonstrate that T. gondii triggers MyD88-independent innate and adaptive immunity in the intestinal mucosa that requires the presence of intestinal microbes. These pathways may be conserved among species and understanding how they work in rodents will likely help determine how humans recognize and respond to T. gondii infection.
登录
查看更多内容
影响因子：
30.3
作者：
Benson A;Pifer R;Behrendt CL;Hooper LV;Yarovinsky F
通讯作者：
Yarovinsky F
对prion感染的独立于MyD88的先天免疫反应的保护作用。
影响因子：
2.3
作者：
Ishibashi D;Atarashi R;Nishida N
通讯作者：
Nishida N
影响因子：
4.4
作者：
Burns, Elia;Eliyahu, Tal;Nussbaum, Gabriel
通讯作者：
Nussbaum, Gabriel
影响因子：
7.7
作者：
Clark JT;Christian DA;Gullicksrud JA;Perry JA;Park J;Jacquet M;Tarrant JC;Radaelli E;Silver J;Hunter CA
通讯作者：
Hunter CA
DOI：
10.4049/jimmunol.1501137
发表时间：
2015-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Cohen SB;Denkers EY
通讯作者：
Denkers EY