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

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 α-galactosylceramide (α-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 α-GalCer treatment before allergen sensitization on Th2 cell responses. We also studied whether α-GalCer's effects require lung Treg cells induced by activated iNKT cells. Our results disclosed that intraperitoneal administration of α-GalCer before allergen sensitization could promote the expansion and suppressive activity of lung CD4⁺FoxP3⁺ 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 α-GalCer on Treg cells mainly require iNKT cells. Moreover, functional inactivation of Treg cells could reverse the inhibitory ability of this α-GalCer therapy on Th2 cell responses in a murine asthma model. Our findings indicate that intraperitoneal administration of α-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.

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