Asthma has been considered an immunological disease mediated by Th2 cells and adaptive immunity. However, clinical and experimental observations suggest that additional pathways may regulate asthma, particularly in non-allergic forms of asthma, such as asthma associated with air pollution, stress, obesity and infection.
Our goal was to understand Th2 cell-independent conditions which might lead to airway hyperreactivity (AHR), a cardinal feature of asthma.
We examined a mouse model of experimental asthma, in which AHR was induced with glycolipid antigens, which activate natural killer T (NKT) cells.
In this model, AHR developed rapidly when mice were treated with NKT cell-activating glycolipid antigens, even in the absence of conventional CD4+ T cells. The activated NKT cells directly induced alveolar macrophages to produce IL-33, which in turn activated NKT cells as well as natural helper cells, a newly described non-T, non-B, innate lymphoid cell type, to increase production of IL-13. Surprisingly, this glycolipid-induced AHR pathway required not only IL-13, but also IL-33 and its receptor, ST2, since it was blocked by an anti-ST2 mAb, and was greatly reduced in ST2−/− mice. When adoptively transferred into IL-13−/− mice, both wildtype natural helper cells and NKT cells were sufficient for the development of glycolipid induced AHR.
Since plant pollens, house dust and some bacteria contain glycolipids that can directly activate NKT cells, these studies suggest that AHR and asthma can fully develop, or be greatly enhanced, through innate immune mechanisms, involving IL-33, natural helper cells and NKT cells.