Memory T cells provide long-lasting protective immunity, and distinct subpopulations of memory T cells drive chronic inflammatory diseases such as asthma. Asthma is a chronic allergic inflammatory disease with airway remodeling including fibrotic changes. The immunological mechanisms that induce airway fibrotic changes remain unknown. We found that interleukin-33 (IL-33) enhanced amphiregulin production by the IL-33 receptor, ST2^hi memory T helper 2 (Th2) cells. Amphiregulin-epidermal growth factor receptor (EGFR)-mediated signaling directly reprogramed eosinophils to an inflammatory state with enhanced production of osteopontin, a key profibrotic immunomodulatory protein. IL-5-producing memory Th2 cells and amphiregulin-producing memory Th2 cells appeared to cooperate to establish lung fibrosis. The analysis of polyps from patients with eosinophilic chronic rhinosinusitis revealed fibrosis with accumulation of amphiregulin-producing CRTH2^hiCD161^hiCD45RO⁺CD4⁺ Th2 cells and osteopontin-producing eosinophils. Thus, the IL-33-amphiregulin-osteopontin axis directs fibrotic responses in eosinophilic airway inflammation and is a potential target for the treatment of fibrosis induced by chronic allergic disorders.

记忆T细胞提供持久的保护性免疫力，记忆T细胞的不同亚群可驱动慢性炎症性疾病，例如哮喘。哮喘是一种慢性过敏性炎性疾病，具有气道重塑，包括纤维化改变。诱导气道纤维化改变的免疫学机制仍然未知。我们发现白介素33（IL-33）通过IL-33受体ST2 ^hi增强了双调蛋白的产生记忆T辅助2细胞（Th2）。两性调节蛋白-表皮生长因子受体（EGFR）介导的信号直接将嗜酸性粒细胞重编程为炎性状态，并增强了骨桥蛋白（一种关键的纤维化免疫调节蛋白）的产生。产生IL-5的记忆Th2细胞和产生双调蛋白的记忆Th2细胞似乎共同建立了肺纤维化。从患者的嗜酸性慢性鼻窦炎息肉的分析揭示纤维化双调蛋白产生CRTH2的积累^喜CD161^喜CD45RO ⁺ CD4 ⁺Th2细胞和产生骨桥蛋白的嗜酸性粒细胞。因此，IL-33-amphiregulin-osteopontin轴指导嗜酸性气道炎症中的纤维化反应，并且是治疗由慢性过敏性疾病引起的纤维化的潜在靶标。