Development and Function of Invariant Natural Killer T Cells Producing TH2- and TH17-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 TH2 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 TH2 (IL-13), TH9 (IL-9 and IL-10), and TH17 (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 TH17 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.

恒定自然杀伤T细胞（invariant natural killer T, iNKT）可依据CD4与IL-17受体B（IL-17RB）的表达模式划分异质性群体；其中IL-17RB是IL-25的受体，而IL-25是TH2型免疫（TH2 immunity）的关键因子。然而，此类iNKT细胞亚型的发育通路与精准功能仍未明确。IL-17RB+iNKT细胞存在于胸腺CD44+/− NK1.1−细胞群中，且即便在IL-15缺失的条件下仍可正常发育——而IL-15是分泌IFN-γ的IL-17RB−iNKT细胞成熟与稳态维持所必需的细胞因子。上述结果提示，iNKT细胞至少包含IL-17RB+与IL-17RB−两个亚群。IL-17RB+iNKT亚型可依据CD4的表达情况，在胸腺与外周组织中进一步分为两个亚群。CD4+ IL-17RB+iNKT细胞可在IL-25的刺激下，以E4BP4依赖的方式分泌TH2型（IL-13）、TH9型（IL-9与IL-10）及TH17型（IL-17A与IL-22）细胞因子；而CD4− IL-17RB+iNKT细胞则为视黄酸受体相关孤儿受体（retinoic acid receptor-related orphan receptor, ROR）γt+亚群，可在IL-23刺激下以E4BP4非依赖的方式分泌TH17型细胞因子。此类IL-17RB+iNKT细胞亚群在稳态状态下大量富集于肺部，并介导病毒诱导的气道高反应性（airway hyperreactivity, AHR）的发病过程。本研究证实，IL-17RB+iNKT细胞亚群的发育路径不同于胸腺内经典iNKT细胞的发育阶段，并在气道疾病的发病机制中发挥重要作用。