Belo Renata, Santarém Nuno, Pereira Cátia, Pérez-Cabezas Begoña, Macedo Fátima, Leite-de-Moraes Maria, Cordeiro-da-Silva Anabela
Parasite Disease Group, Institute for Molecular and Cell Biology (IBMC), Institute for Investigation and Innovation in Health (i3S), Porto, Portugal.
Laboratory of Immunoregulation and Immunopathology, Institut Necker-Enfants Malades, CNRS UMR 8253 and INSERM UMR 1151, Paris, France.
Front Immunol. 2017 Jun 19;8:710. doi: 10.3389/fimmu.2017.00710. eCollection 2017.
is one of the major parasite species associated with visceral leishmaniasis, a severe form of the disease that can become lethal if untreated. This obligate intracellular parasite has developed diverse strategies to escape the host immune response, such as exoproducts (Exo) carrying a wide range of molecules, including parasite virulence factors, which are potentially implicated in early stages of infection. Herein, we report that Exo and its two fractions composed of extracellular vesicles (EVs) and vesicle-depleted-exoproducts (VDEs) inhibit human peripheral blood invariant natural killer T (iNKT) cell expansion in response to their specific ligand, the glycolipid α-GalactosylCeramide (α-GalCer), as well as their capacity to promptly produce IL-4 and IFNγ. Using plate-bound CD1d and α-GalCer, we found that Exo, EV, and VDE fractions reduced iNKT cell activation in a dose-dependent manner, suggesting that they prevented α-GalCer presentation by CD1d molecules. This direct effect on CD1d was confirmed by the observation that CD1d:α-GalCer complex formation was impaired in the presence of Exo, EV, and VDE fractions. Furthermore, lipid extracts from the three compounds mimicked the inhibition of iNKT cell activation. These lipid components of exoproducts, including EV and VDE fractions, might compete for CD1-binding sites, thus blocking iNKT cell activation. Overall, our results provide evidence for a novel strategy through which can evade immune responses of mammalian host cells by preventing iNKT lymphocytes from recognizing glycolipids in a TCR-dependent manner.
是与内脏利什曼病相关的主要寄生虫物种之一，内脏利什曼病是该疾病的一种严重形式，若不治疗可能会致命。这种专性细胞内寄生虫已发展出多种策略来逃避宿主免疫反应，例如携带多种分子的外产物（Exo），包括寄生虫毒力因子，这些分子可能与感染的早期阶段有关。在此，我们报告Exo及其由细胞外囊泡（EVs）和无囊泡外产物（VDEs）组成的两个部分抑制人外周血不变自然杀伤T（iNKT）细胞对其特异性配体糖脂α-半乳糖神经酰胺（α-GalCer）的反应而发生的扩增，以及它们迅速产生白细胞介素-4和干扰素γ的能力。使用包被在平板上的CD1d和α-GalCer，我们发现Exo、EV和VDE部分以剂量依赖的方式降低iNKT细胞的活化，这表明它们阻止了CD1d分子呈递α-GalCer。在存在Exo、EV和VDE部分的情况下，CD1d:α-GalCer复合物形成受损，这一观察结果证实了对CD1d的这种直接作用。此外，这三种化合物的脂质提取物模拟了对iNKT细胞活化的抑制作用。外产物的这些脂质成分，包括EV和VDE部分，可能竞争CD1结合位点，从而阻断iNKT细胞的活化。总体而言，我们的结果为一种新策略提供了证据，通过该策略，（寄生虫）可以通过阻止iNKT淋巴细胞以TCR依赖的方式识别糖脂来逃避哺乳动物宿主细胞的免疫反应。
