α-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 ␣-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 cellknockout 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 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 ␣-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.

Research progress of icariin, an extract of traditional Chinese medicine, in the treatment of asthma

“…Regulatory T cells (Tregs) are CD4+T cells that are critical to the development and homeostasis of Th2 cells. 32 The decrease in Treg cells and the increase in the number of Th17 cells in asthma patients are important pathogenic mechanisms of asthma and one of the main research directions for clinical treatment. 33 Experiments by Ying Wei et al suggest that the traditional Chinese medicines Epimedium and Astragalus may play an important role in inhibiting TH17-related inflammatory factors, such as IL-6 and IL-10, and promoting Treg cell-related factors such as FOXP3, providing a new treatment direction to improve the imbalanced ratio of TH17/Treg cells in asthma.…”

iNKT cells with high PLZF expression are recruited into the lung via CCL21‐CCR7 signaling to facilitate the development of asthma tolerance in mice

“…Recently, a few studies have suggested the potential role of iNKT cells in suppressing asthma inflammation. For instance, iNKT cells could mediate induction of Tregs, this evidence was supported by findings that intraperitoneal administration of α‐GalCer before allergen sensitization could promote the expansion and suppressive activity of lung CD4 + FoxP3 + Treg cells [24‐26]. These effects could suppress regulated Th2‐cell responses and decrease maturation of lung DCs [24].…”

“…For instance, iNKT cells could mediate induction of Tregs, this evidence was supported by findings that intraperitoneal administration of α‐GalCer before allergen sensitization could promote the expansion and suppressive activity of lung CD4 + FoxP3 + Treg cells [24‐26]. These effects could suppress regulated Th2‐cell responses and decrease maturation of lung DCs [24]. However, the relationship between CCL21‐CCR7 and iNKT recruited in tolerant lung and if RSV infection could impair tolerance by inhibiting iNKT recruitment are not well‐defined yet.…”

“…The latest studies have suggested that iNKT cells also contribute to tolerance to cow's milk in children [22, 23]. Treatment with alpha‐galactosylceramide (α‐GalCer) combined with CD1d, a specific marker of iNKT cells, before allergen sensitization can prevent T‐helper 2 (Th2) cell responses, promoting iNKT cell‐mediated induction of Tregs and inducing peripheral tolerance in asthma [24‐26]. Thus, PLZF‐expressing iNKT cells might be a novel target for studying asthma tolerance establishment and disruption.…”

Wuhu Decoction Regulates Dendritic Cell Autophagy in the Treatment of Respiratory Syncytial Virus (RSV)-Induced Mouse Asthma by AMPK/ULK1 Signaling Pathway

“…CD4 + CD25 + regulatory T cells (CD4 + CD25 + Treg) play an important role in the development of bronchial asthma [12]. Recent studies have shown that by promoting the expansion and activity of lung CD4 + CD25 + T cells, mice Th2 cell responses can be downregulated and immunogenic maturation of lung DCs can be reduced [13]. This study found that compared with the control group, the CD8 + T cells in the asthma group were significantly elevated, and the number of CD4 + CD25 + T cells was significantly downregulated.…”