Invariant NKT Cells Act as an Adjuvant to Enhance Th2 Inflammatory Response in an OVA-Induced Mouse Model of Asthma

Abstract

BackgroundInvariant natural killer T cells (iNKT cells) are a unique subset of T lymphocytes and are considered to play an important role in the development of allergic bronchial asthma. Recently, iNKT cells were shown to play an immunoregulatory role in CD4+ and CD8+ T cell-mediated adaptive immune response. Allergen-specific Th2 inflammatory responses are an important part of the adaptive immune response in asthma. However, the regulatory functions of the Th2 inflammatory response in asthma have not been studied in detail.MethodIn this study, we have investigated the regulatory functions of iNKT cells on the Th2 inflammatory response in an ovalbumin (OVA)-induced murine model of asthma.ResultsOur results demonstrate that α-Galactosylceramide (α-GalCer) administration activated iNKT cells but could not induce the Th2 inflammatory response in wild-type (WT) mice. In the OVA-induced asthma model, α-GalCer administration and adoptive transfer of iNKT cells significantly augmented the Th2 inflammatory responses, including elevated inflammatory cell infiltration in the lung and bronchoalveolar lavage fluid (BALF); increased levels of IL-4, IL-5, and IL-13 in the BALF and splenocyte culture supernatant; and increased serum levels of OVA-specific IgE and IgG1. In addition, the Th2 inflammatory response was reduced, but not completely abrogated in CD1d-/- mice immunized and challenged with OVA, compared with WT mice.ConclusionThese results suggest that iNKT cells may serve as an adjuvant to enhance Th2 inflammatory response in an OVA-induced murine model of asthma.

α‐galactosylceramide generates lung regulatory T cells through the activated natural killer T cells in mice

“…Therefore, it is probable that lung CD4 + FoxP3 + Treg cells induced by the activated iNKT cells with intraperitoneal administration of α‐GalCer in turn may be necessary to down‐regulate the activation of iNKT cells and restore them to homeostatic conditions. However, our present results sharply differ from our previous findings showing that intraperitoneal administration of α‐GalCer prior to allergen challenge can promote Th2 response through inducing immunogenic maturation of lung dendritic cells (LDCs) in mouse models of asthma . Therefore, our findings supported the notion that the opposite role of iNKT cells activated by α‐GalCer in different pathological settings may be partially related to the timing of α‐GalCer administration .…”

“…As such, our present study uses CD1d −/− mice to investigate whether iNKT cells activated by α‐GalCer contribute to the generation of lung Treg cells induced by α‐GalCer. In our previous and present study, intraperitoneal injection of α‐GalCer can induce the activation of lung iNKT cells, but the activation of iNKT cells by α‐GalCer do not result in airway inflammation in WT mice without OVA sensitization and challenge . As reported by Meyer et al., it seemed that the activation state of iNKT cells may play an important role in the pathogeneses of AHR and airway inflammation, and that α‐GalCer can lead to iNKT cell anergy, which can suppress the subsequent initiation of AHR and airway inflammation in WT mice .…”

“…Mice were euthanized and lungs were lavaged by a catheter with a total volume of 1.5 mL PBS containing 1 mmol/L sodium EDTA, which was followed by lung resection, as previously described. 12 The levels of IL-2, IL-4, IL-5, IL-10, IL-13 and IFN-γ in the supernatants were assessed by ELISA according to the manufacturer's instructions (eBioscience). Cells recovered from the BALF were collected and stained with May-Grunwald Giemsa (Jiancheng, Nanjing, China) for differential cell counting.…”

“…10,11 In our previous study, we found that intraperitoneal administration of α-GalCer had the ability to stimulate iNKT cells, but α-GalCer-activated iNKT cells do not elicit airway inflammation in wild-type (WT) mice in the absence of ovalbumin (OVA) immunization and challenge. 12 At present, it is proposed that iNKT cells have the capacity to induce Treg cells, which give rise to peripheral tolerance. 8,9 Thus, it was hypothesized that intraperitoneal administration of α-GalCer may induce the generation of lung Treg cells through the activation of iNKT cells in naive mice.…”

Spectrum of T‐lymphocyte activities regulating allergic lung inflammation

“…304 In experimental asthma, iNKT cells were shown to enhance Th2 responses through adjuvant effects and obesity-induced functional upregulation of iNKT cells, which augmented Th2 cytokine responses. 305,306 Whether iNKT cells are activated in asthmatics and whether the pathogenic effects of activated iNKT cells that were observed in mice are reproducible in human asthma remain to be determined. 307…”