Interleukin-33 (IL-33) is a pleiotropic cytokine that can promote type 2 inflammation but also drives immunoregulation through Foxp3⁺T_reg expansion. How IL-33 is exported from cells to serve this dual role in immunosuppression and inflammation remains unclear. Here, we demonstrate that the biological consequences of IL-33 activity are dictated by its cellular source. Whereas IL-33 derived from epithelial cells stimulates group 2 innate lymphoid cell (ILC2)–driven type 2 immunity and parasite clearance, we report that IL-33 derived from myeloid antigen-presenting cells (APCs) suppresses host-protective inflammatory responses. Conditional deletion of IL-33 in CD11c-expressing cells resulted in lowered numbers of intestinal Foxp3⁺T_reg cells that express the transcription factor GATA3 and the IL-33 receptor ST2, causing elevated IL-5 and IL-13 production and accelerated anti-helminth immunity. We demonstrate that cell-intrinsic IL-33 promoted mouse dendritic cells (DCs) to express the pore-forming protein perforin-2, which may function as a conduit on the plasma membrane facilitating IL-33 export. Lack of perforin-2 in DCs blocked the proliferative expansion of the ST2⁺Foxp3⁺T_reg subset. We propose that perforin-2 can provide a plasma membrane conduit in DCs that promotes the export of IL-33, contributing to mucosal immunoregulation under steady-state and infectious conditions.

白细胞介素-33 (IL-33) 是一种多效性细胞因子，可以促进 2 型炎症，但也可以通过 Foxp3 ⁺ T _reg扩增来驱动免疫调节。IL-33 如何从细胞中输出以在免疫抑制和炎症中发挥这种双重作用仍不清楚。在这里，我们证明 IL-33 活性的生物学后果是由其细胞来源决定的。虽然源自上皮细胞的 IL-33 刺激第 2 组先天淋巴细胞 (ILC2) 驱动的 2 型免疫和寄生虫清除，但我们报告说，源自髓样抗原呈递细胞 (APC) 的 IL-33 抑制宿主保护性炎症反应。CD11c 表达细胞中 IL-33 的条件性缺失导致肠道 Foxp3 ⁺ T _{reg 数量减少}表达转录因子 GATA3 和 IL-33 受体 ST2 的细胞，导致 IL-5 和 IL-13 产生增加并加速抗蠕虫免疫。我们证明细胞内在的 IL-33 促进小鼠树突细胞 (DC) 表达成孔蛋白 perforin-2，它可以作为质膜上的管道，促进 IL-33 输出。DCs 中缺乏 perforin-2 阻止了 ST2 ⁺ Foxp3 ⁺ T _reg子集的增殖。我们建议穿孔素 2 可以在 DC 中提供质膜导管，促进 IL-33 的输出，有助于稳态和感染条件下的粘膜免疫调节。