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

• Published in: The Journal of biological chemistry 2019-04, Vol.294 (14), p.5438-5455
• Main Authors: Chen, Qianhui, Guo, Xuxue, Deng, Nishan, Liu, Linlin, Chen, Shuo, Wang, Ailing, Li, Ruiyun, Huang, Yi, Ding, Xuhong, Yu, Hongying, Hu, Suping, Nie, Hanxiang
• Format: Article
• Language: English
• Subjects: allergen; Allergens - immunology; Allergens - toxicity; allergy; Animals; antibody; antigen; asthma; Asthma - chemically induced; Asthma - immunology; Asthma - pathology; Asthma - prevention & control; cellular immune response; cytokine response; Dendritic Cells - immunology; Dendritic Cells - pathology; Disease Models, Animal; Female; Galactosylceramides - pharmacology; Immunology; inflammation; invariant NKT cells; lung disease; Mice; Mice, Inbred BALB C; Mice, Knockout; Natural Killer T-Cells - immunology; Natural Killer T-Cells - pathology; Pyroglyphidae - immunology; regulatory T cells; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - pathology; Th2 cell response; Th2 Cells - immunology; Th2 Cells - pathology; α-galactosylceramide
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA118.005418

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.