γ-Galactosylceramide treatment before allergen sensitization promotes iNKT cell mediated induction of Treg cells, preventing Th2 cell responses in murine asthma

Abstract

Asthma is a common inflammatory pulmonary disorder involving a diverse array of immune cells such as proinflammatory T helper 2 (Th2) cells. We recently reported that intraperitoneal injection of γ-Galactosylceramide (-GalCer) can stimulate the lung invariant natural killer T (iNKT) cells and does not lead to airway inflammation in WT mice. Other studies indicate that iNKT cells play an important role in inducing regulatory T cells (Treg cells) and peripheral tolerance. Using iNKT cell knockout mice, functional inactivation of Treg cells, and co-culture experiments in murine asthma models, we investigated the immunoregulatory effects of -GalCer treatment before allergen sensitization on Th2 cell responses. We also studied whether -GalCer's effects require lung Treg cells induced by activated iNKT cells. Our results disclosed that intraperitoneal administration of -GalCer before allergen sensitization could promote the expansion and suppressive activity of lung CD4FoxP3 Treg cells. These effects were accompanied by down-regulated Th2 cell responses and decreased immunogenic maturation of lung dendritic cells in WT mice. However, these changes were absent in CD1d/ mice immunized and challenged with ovalbumin or house dust mites, indicating that the effects of -GalCer on Treg cells mainly require iNKT cells. Moreover, functional inactivation of Treg cells could reverse the inhibitory ability of this -GalCer therapy on Th2 cell responses in a murine asthma model. Our findings indicate that intraperitoneal administration of -GalCer before the development of asthma symptoms induces the generation of lung Treg cells via iNKT cells and may provide a potential therapeutic strategy to prevent allergic asthma.