IL-33 induces antigen-specific IL-5+ T cells and promotes allergic-induced airway inflammation independent of IL-4

Type 2 cytokines (IL-4, IL-5, and IL-13) play a pivotal role in helminthic infection and allergic disorders. CD4(+) T cells which produce type 2 cytokines can be generated via IL-4-dependent and -independent pathways. Although the IL-4-dependent pathway is well documented, factors that drive IL-4-independent Th2 cell differentiation remain obscure. We report here that the new cytokine IL-33, in the presence of Ag, polarizes murine and human naive CD4(+) T cells into a population of T cells which produce mainly IL-5 but not IL-4. This polarization requires IL-1R-related molecule and MyD88 but not IL-4 or STAT6. The IL-33-induced T cell differentiation is also dependent on the phosphorylation of MAPKs and NF-kappa B but not the induction of GATA3 or T-bet. In vivo, ST2(-/-) mice developed attenuated airway inflammation and IL-5 production in a murine model of asthma. Conversely, IL-33 administration induced the IL-5-producing T cells and exacerbated allergen-induced airway inflammation in wild-type as well as IL-4(-/-) mice. Finally, adoptive transfer of IL-33-polarized IL-5(+)IL-4(-) T cells triggered airway inflammation in naive IL-4(-/-) mice. Thus, we demonstrate here that, in the presence of Ag, IL-33 induces IL-5-producing T cells and promotes airway inflammation independent of IL-4.

2型细胞因子（白细胞介素 - 4、白细胞介素 - 5和白细胞介素 - 13）在蠕虫感染和过敏性疾病中起关键作用。产生2型细胞因子的CD4(+) T细胞可通过白细胞介素 - 4依赖和非依赖途径产生。尽管白细胞介素 - 4依赖途径已有充分记载，但驱动白细胞介素 - 4非依赖的Th2细胞分化的因素仍不清楚。我们在此报道，在有抗原存在的情况下，新型细胞因子白细胞介素 - 33可使小鼠和人类初始CD4(+) T细胞极化为主要产生白细胞介素 - 5而不产生白细胞介素 - 4的T细胞群。这种极化需要白细胞介素 - 1受体相关分子和髓样分化因子88，但不需要白细胞介素 - 4或信号转导及转录激活因子6。白细胞介素 - 33诱导的T细胞分化还依赖于丝裂原活化蛋白激酶和核因子 - κB的磷酸化，但不依赖于GATA结合蛋白3或T - 细胞诱导蛋白的诱导。在体内，在哮喘小鼠模型中，ST2基因敲除小鼠气道炎症减轻且白细胞介素 - 5产生减少。相反，给予白细胞介素 - 33可在野生型以及白细胞介素 - 4基因敲除小鼠中诱导产生白细胞介素 - 5的T细胞，并加剧过敏原诱导的气道炎症。最后，过继转移白细胞介素 - 33极化的白细胞介素 - 5(+)白细胞介素 - 4(-) T细胞可在初始白细胞介素 - 4基因敲除小鼠中引发气道炎症。因此，我们在此证明，在有抗原存在的情况下，白细胞介素 - 33可诱导产生白细胞介素 - 5的T细胞，并促进不依赖白细胞介素 - 4的气道炎症。