Lymphoid cells that produce interleukin (IL)-17 cytokines protect barrier tissues from pathogenic microbes but are also prominent effectors of inflammation and autoimmune disease. T helper 17 (Th17) cells, defined by RORγt-dependent production of IL-17A and IL-17F, exert homeostatic functions in the gut upon microbiota-directed differentiation from naive CD4+ T cells. In the non-pathogenic setting, their cytokine production is regulated by serum amyloid A proteins (SAA1 and SAA2) secreted by adjacent intestinal epithelial cells. However, Th17 cell behaviors vary markedly according to their environment. Here, we show that SAAs additionally direct a pathogenic pro-inflammatory Th17 cell differentiation program, acting directly on T cells in collaboration with STAT3-activating cytokines. Using loss- and gain-of-function mouse models, we show that SAA1, SAA2, and SAA3 have distinct systemic and local functions in promoting Th17-mediated inflammatory diseases. These studies suggest that T cell signaling pathways modulated by the SAAs may be attractive targets for anti-inflammatory therapies.

中文翻译：

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血清淀粉样蛋白 A 诱导致病性 Th17 细胞并促进炎症性疾病。

产生白细胞介素 (IL)-17 细胞因子的淋巴样细胞可保护屏障组织免受病原微生物的侵害，但也是炎症和自身免疫性疾病的重要效应物。由 RORγt 依赖性产生的 IL-17A 和 IL-17F 定义的 T 辅助 17 (Th17) 细胞在微生物群指导的幼稚 CD4+ T 细胞分化后在肠道中发挥稳态功能。在非致病环境中，它们的细胞因子产生受相邻肠上皮细胞分泌的血清淀粉样蛋白 A 蛋白（SAA1 和 SAA2）的调节。然而，Th17 细胞的行为因环境而异。在这里，我们显示 SAA 还指导致病性促炎 Th17 细胞分化程序，与 STAT3 激活细胞因子合作直接作用于 T 细胞。使用功能损失和获得功能的鼠标模型，我们表明 SAA1、SAA2 和 SAA3 在促进 Th17 介导的炎症性疾病方面具有不同的全身和局部功能。这些研究表明，由 SAA 调节的 T 细胞信号通路可能是抗炎治疗的有吸引力的靶点。