Development and function of invariant natural killer T cells producing T _H2- and T _H17-cytokines

There is heterogeneity in invariant natural killer T (iNKT) cells based on the expression of CD4 and the IL-17 receptor B (IL-17RB), a receptor for IL-25 which is a key factor in T _H2 immunity. However, the development pathway and precise function of these iNKT cell subtypes remain unknown. IL-17RB ⁺ iNKT cells are present in the thymic CD44 ^+/- NK1.1 ^- population and develop normally even in the absence of IL-15, which is required for maturation and homeostasis of IL-17RB ^- iNKT cells producing IFN-γ. These results suggest that iNKT cells contain at least two subtypes, IL-17RB ⁺ and IL-17RB ^- subsets. The IL-17RB ⁺ iNKT subtypes can be further divided into two subtypes on the basis of CD4 expression both in the thymus and in the periphery. CD4 ⁺ IL-17RB ⁺ iNKT cells produce T _H2 (IL-13), T _H9 (IL-9 and IL-10), and T _H17 (IL-17A and IL-22) cytokines in response to IL-25 in an E4BP4-dependent fashion, whereas CD4 ^- IL-17RB ⁺ iNKT cells are a retinoic acid receptor-related orphan receptor (ROR)γt ⁺ subset producing T _H17 cytokines upon stimulation with IL-23 in an E4BP4-independent fashion. These IL-17RB ⁺ iNKT cell subtypes are abundantly present in the lung in the steady state and mediate the pathogenesis in virus-induced airway hyperreactivity (AHR). In this study we demonstrated that the IL-17RB ⁺ iNKT cell subsets develop distinct from classical iNKT cell developmental stages in the thymus and play important roles in the pathogenesis of airway diseases.