α-Galactosylceramide, a Ligand of Natural Killer T Cells, Inhibits Allergic Airway Inflammation

Abstract

alpha-Galactosylceramide (alpha-GalCer) is a specific ligand of natural killer T cells (NKT cells) that regulates the immune responses such as tumor rejection and autoimmunity by producing interferon (IFN)-gamma and interleukin (IL)-4. However, it has not been determined whether alpha-GalCer-activated NKT cells modulate allergic inflammation. Because alpha-GalCer induces a large amount of IFN-gamma production by NKT cells, we hypothesized that an in vivo administration of alpha-GalCer could inhibit allergic airway inflammation in mice. Strikingly, a single intraperitoneal injection of alpha-GalCer almost completely abrogated an infiltrate with eosinophils in the lung tissue as well as in the bronchoalveolar lavage. This inhibition of allergic inflammation was associated with a significant decrease in the levels of IL-4, IL-5, and IL-13 in bronchoalveolar lavage fluid and in the number of goblet cells. In addition, this ligand significantly inhibited airway hyperresponsiveness to inhaled methacholine and raised the serum levels of ovalbumin-specific IgG2a with a decrease in those of ovalbumin-specific IgE. In IFN-gamma knockout mice, however, alpha-GalCer failed to exert such inhibitory effects in this asthma model. These results indicate that alpha-GalCer prevents allergic airway inflammation possibly through IFN-gamma production by ligand-activated NKT cells, suggesting the potential therapeutic application of alpha-GalCer in asthma.

Glycolipid activation of invariant T cell receptor + NK T cells is sufficient to induce airway hyperreactivity independent of conventional CD4 + T cells

“…␣-GalCer is known to induce iNKT cell anergy in a manner similar to T cells treated with superantigens (18), although ␣-GalCer may also alter other factors such as iNKT cell trafficking or cytokine production to prevent subsequent AHR. The attenuated AHR observed with two doses of ␣-GalCer may be similar to recent reports showing that administration of ␣-GalCer to mice already sensitized to ovalbumin (OVA) prevented the subsequent development of AHR (19)(20)(21). However, in a similar OVA-induced AHR system, we found that administration of ␣-GalCer just before airway challenge with OVA resulted first in exacerbation of AHR, measured 48 h after the ␣-GalCer challenge, although AHR measured 96 h after the ␣-GalCer administration was reduced (Fig.…”

“…Although we found that administration of ␣-GalCer directly induces AHR, several groups recently found that administration of ␣-GalCer 24 h before challenge with OVA inhibited allergeninduced AHR (19)(20)(21). In contrast, other investigators have found that coadministration of ␣-GalCer with antigen sensitizes mice to these antigens, thereby enhancing AHR (38,39).…”

Plasticity of Invariant NKT Cell Regulation of Allergic Airway Disease Is Dependent on IFN-γ Production

“…Systemic administration of aGalCer, a specific ligand for iNK-T cells, was shown to prevent the development of allergic airway inflammation and AHR under certain conditions (25,27,28). However, these findings could not distinguish whether the effects were manifested during the initiation phase of the response or specifically altered the subsequent airway response to allergen challenge.…”

“…In previously sensitized mice, IFN-g was shown to be critical to the inhibition of allergic airway inflammation and AHR induced by aGalCer (25,27,28). To determine whether transfer of OVA BMDCs exposed to aGalCer modulated the numbers of iNKT cells in the lung and their capacity for IFN-g production, we quantified the number of iNKT cells in the lungs and the numbers of IFN-gproducing iNKT cells by intracellular cytokine staining.…”

“…administration of aGalCer prior to Ag challenge of sensitized mice inhibits allergic airway inflammation and AHR through iNKT cells and in an IFN-gdependent manner (25,27,28). It is unclear whether such effects are restricted to the challenge phase or whether activation of iNKT cells during the sensitization (initiation) phase also regulates development of allergic inflammation and AHR, because they were shown to be a potent producers of Th1-and Th2-type proinflammatory cytokines (29).…”