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Leishmania infantum Exoproducts Inhibit Human Invariant NKT Cell Expansion and Activation.

ABSTRACT: Leishmania infantum 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 L. infantum 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 ?-GalactosylCeramide (?-GalCer), as well as their capacity to promptly produce IL-4 and IFN?. Using plate-bound CD1d and ?-GalCer, we found that Exo, EV, and VDE fractions reduced iNKT cell activation in a dose-dependent manner, suggesting that they prevented ?-GalCer presentation by CD1d molecules. This direct effect on CD1d was confirmed by the observation that CD1d:?-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 L. infantum 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 L. infantum can evade immune responses of mammalian host cells by preventing iNKT lymphocytes from recognizing glycolipids in a TCR-dependent manner.

SUBMITTER: Belo R

PROVIDER: S-EPMC5474685 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Leishmania infantum Exoproducts Inhibit Human Invariant NKT Cell Expansion and Activation.

Belo Renata R Santarém Nuno N Pereira Cátia C Pérez-Cabezas Begoña B Macedo Fátima F Leite-de-Moraes Maria M Cordeiro-da-Silva Anabela A

Frontiers in immunology 20170619

Leishmania infantum 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 L. infantum Exo and its two fra ...[more]

PMID: 28674535

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Project description:Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide. Although intra-amniotic infection is a recognized cause of spontaneous preterm labor, the noninfection-related etiologies are poorly understood. In this article, we demonstrated that the expansion of activated CD1d-restricted invariant NKT (iNKT) cells in the third trimester by administration of ?-galactosylceramide (?-GalCer) induced late PTB and neonatal mortality. In vivo imaging revealed that fetuses from mice that underwent ?-GalCer-induced late PTB had bradycardia and died shortly after delivery. Yet, administration of ?-GalCer in the second trimester did not cause pregnancy loss. Peroxisome proliferator-activated receptor (PPAR)? activation, through rosiglitazone treatment, reduced the rate of ?-GalCer-induced late PTB and improved neonatal survival. Administration of ?-GalCer in the third trimester suppressed PPAR? activation, as shown by the downregulation of Fabp4 and Fatp4 in myometrial and decidual tissues, respectively; this suppression was rescued by rosiglitazone treatment. Administration of ?-GalCer in the third trimester induced an increase in the activation of conventional CD4(+) T cells in myometrial tissues and the infiltration of activated macrophages, neutrophils, and mature dendritic cells to myometrial and/or decidual tissues. All of these effects were blunted after rosiglitazone treatment. Administration of ?-GalCer also upregulated the expression of inflammatory genes at the maternal-fetal interface and systemically, and rosiglitazone treatment partially attenuated these responses. Finally, an increased infiltration of activated iNKT-like cells in human decidual tissues is associated with noninfection-related preterm labor/birth. Collectively, these results demonstrate that iNKT cell activation in vivo leads to late PTB by initiating innate and adaptive immune responses and suggest that the PPAR? pathway has potential as a target for prevention of this syndrome.

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Leishmania infantum Exoproducts Inhibit Human Invariant NKT Cell Expansion and Activation.

Publications

<i>Leishmania infantum</i> Exoproducts Inhibit Human Invariant NKT Cell Expansion and Activation.

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