Background 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. Objectives Our goal was to understand Th2 cell-independent conditions which might lead to airway hyperreactivity (AHR), a cardinal feature of asthma. Methods We examined a mouse model of experimental asthma, in which AHR was induced with glycolipid antigens, which activate natural killer T (NKT) cells. Results 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. Conclusion 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.

The role of Th17 cells in type I diabetes (TID) remains largely unknown. Glutamic acid decarboxylase (GAD) sequence 206–220 (designated GAD2) represents a late-stage epitope, but GAD2-specific T cell receptor transgenic T cells producing interferon γ (IFNγ) protect against passive TID. Because IFNγ is known to inhibit Th17 cells, effective presentation of GAD2 peptide under noninflammatory conditions may protect against TID at advanced disease stages. To test this premise, GAD2 was genetically incorporated into an immunoglobulin (Ig) molecule to magnify tolerance, and the resulting Ig-GAD2 was tested against TID at different stages of the disease. The findings indicated that Ig-GAD2 could not prevent TID at the preinsulitis phase, but delayed TID at the insulitis stage. More importantly, Ig-GAD2 sustained both clearance of pancreatic cell infiltration and β-cell division and restored normoglycemia when given to hyperglycemic mice at the prediabetic stage. This was dependent on the induction of splenic IFNγ that inhibited interleukin (IL)-17 production. In fact, neutralization of IFNγ led to a significant increase in the frequency of Th17 cells, and the treatment became nonprotective. Thus, IFNγ induced by an adjuvant free antigen, contrary to its usual inflammatory function, restores normoglycemia, most likely by localized bystander suppression of pathogenic IL-17–producing cells.

Primary neonatal T cell responses comprise both T helper (

No abstract