Redundant Notch1 and Notch2 signaling is necessary for IFNγ secretion by T helper 1 cells during infection with Leishmania major.
Redundant Notch1 and Notch2 signaling is necessary for IFNγ secretion by T helper 1 cells during infection with Leishmania major.
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DOI：
10.1371/journal.ppat.1002560
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Tacchini-Cottier F
中科院分区：
文献类型：
--
作者：
Auderset F;Schuster S;Coutaz M;Koch U;Desgranges F;Merck E;MacDonald HR;Radtke F;Tacchini-Cottier F
对细胞内寄生虫的保护性免疫应答在大多数情况下涉及分泌IFNγ的CD 4+辅助性T（Th）1细胞的分化。Notch受体在发育过程中调节细胞分化，但其在外周CD 4 + T辅助1细胞极化中的意义尚不清楚。在四种Notch受体中，只有Notch 1（N1）和Notch 2（N2）在活化的CD 4 + T细胞上表达。为了研究Notch在寄生虫感染后Th 1细胞分化中的作用，用原生动物寄生虫硕大利什曼原虫感染具有N1、N2或两者（N1 N2 Δ CD 4Cre）的T细胞特异性基因消除的小鼠。N1 N2 Δ CD 4Cre小鼠，C57 BL/6 L。主要耐药遗传背景，发展不愈合的病变和不受控制的寄生虫血症。易感性与引流淋巴结CD 4 + T细胞分泌IFNγ受损以及IL-5和IL-13 Th 2细胞因子分泌增加相关。在其T细胞中N1或N2单一失活的小鼠对感染具有抗性，并产生保护性Th 1免疫应答，表明N1或N2的CD 4 + T细胞表达在驱动Th 1分化中是多余的。此外，我们表明Notch信号传导是Th 1细胞分泌IFNγ所必需的。这种作用不依赖于Notch受体的主要效应子CSL/RBP-Jκ，因为L. T细胞中RBP-Jκ缺失的主要感染小鼠能够产生分泌IFNγ的Th 1细胞，杀死寄生虫并治愈其病变。总的来说，我们在这里证明了RBP-Jκ非依赖性Notch信号传导在L.严重感染利什曼原虫属的原生动物寄生虫感染导致人类和哺乳动物的一系列局部或全身性疾病。总的来说，利什曼病在全世界88个国家中折磨着大约1200万人。皮肤利什曼病是最普遍的形式的疾病。为了更好地理解导致对皮肤形式的疾病的保护的复杂分子途径，我们使用了硕大利什曼原虫小鼠模型。大多数小鼠品系控制L.由于Th 1应答的发展，导致T细胞分泌IFNγ，从而促进愈合和抵抗再感染。Notch信号通路在细胞分化和细胞命运决定的调控中是非常保守的通路。然而，Notch受体在寄生虫感染应答中的作用尚不清楚。在这项研究中，我们感染了T细胞表面不表达Notch 1和Notch 2受体的小鼠。我们表明，这些Notch受体是保护性Th 1免疫反应对L。少校这些结果有助于了解参与对病原体的保护性反应的发展机制。
The protective immune response to intracellular parasites involves in most cases the differentiation of IFNγ-secreting CD4+ T helper (Th) 1 cells. Notch receptors regulate cell differentiation during development but their implication in the polarization of peripheral CD4+ T helper 1 cells is not well understood. Of the four Notch receptors, only Notch1 (N1) and Notch2 (N2) are expressed on activated CD4+ T cells. To investigate the role of Notch in Th1 cell differentiation following parasite infection, mice with T cell-specific gene ablation of N1, N2 or both (N1N2ΔCD4Cre) were infected with the protozoan parasite Leishmania major. N1N2ΔCD4Cre mice, on the C57BL/6 L. major-resistant genetic background, developed unhealing lesions and uncontrolled parasitemia. Susceptibility correlated with impaired secretion of IFNγ by draining lymph node CD4+ T cells and increased secretion of the IL-5 and IL-13 Th2 cytokines. Mice with single inactivation of N1 or N2 in their T cells were resistant to infection and developed a protective Th1 immune response, showing that CD4+ T cell expression of N1 or N2 is redundant in driving Th1 differentiation. Furthermore, we show that Notch signaling is required for the secretion of IFNγ by Th1 cells. This effect is independent of CSL/RBP-Jκ, the major effector of Notch receptors, since L. major-infected mice with a RBP-Jκ deletion in their T cells were able to develop IFNγ-secreting Th1 cells, kill parasites and heal their lesions. Collectively, we demonstrate here a crucial role for RBP-Jκ-independent Notch signaling in the differentiation of a functional Th1 immune response following L. major infection. Infection with protozoan parasites of Leishmania species results in a spectrum of local or systemic diseases in humans and mammals. Overall, leishmaniasis afflicts around 12 million individuals in 88 countries worldwide. Cutaneous leishmaniasis is the most prevalent form of the disease. In order to better understand the complex molecular pathways leading to protection against the cutaneous form of the disease, we used the Leishmania major mouse model. Most mouse strains control L. major infection due to the development of a Th1 response, leading to secretion of IFNγ by T cells which promotes healing and resistance to reinfection. Notch signaling is a very conserved pathway in the regulation of cell differentiation and cell fate decision. However the contribution of Notch receptors in the response to parasite infection is not clear. In this study, we infected mice that do not express Notch1 and Notch2 receptors on the surface of their T cells. We show that these Notch receptors are key players in the development of a protective Th1 immune response against L. major. These results contribute to the understanding of the mechanisms involved in the development of a protective response against pathogens.