Ulcerative Colitis (UC) is a chronic gastrointestinal condition with high morbidity. While modern medical therapies have revolutionized the care of UC, 10-25% of patients fail medications and still progress to surgery. Thus, developing new treatments is a core problem in UC. T-cells, especially Th17 cells, are strongly linked with UC and are major targets of medications in UC. Tissue-resident memory T-cells (TRM) are a distinct class of T-cells that are highly enriched in the intestine, closely aligned with the microbiota, and are implicated in the pathogenesis of UC. Unlike circulating T-cells, TRM are difficult to target because they do not recirculate. Thus, we focused on cytokines like IL-15 which act as a tissue danger signal and regulate T-cells in situ. We found that the IL-15 axis is upregulated in UC and predicts treatment response. IL-15 was redundant for Th17 differentiation but could activate terminally differentiated Th17 cells to promote intestinal inflammation. Finally, in CD4+ TRM from patients with UC, IL-15 upregulated RORC, the master transcription factor for Th17 cells, via a Janus Kinase (JAK)1 pathway. Thus, IL-15 promotes terminally differentiated inflammatory Th17 cells in the intestine raising the possibility that IL-15 may be a target for UC treatments.

中文翻译：

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IL-15促进肠道炎症性Th17细胞

溃疡性结肠炎 (UC) 是一种慢性胃肠道疾病，发病率很高。虽然现代医学疗法彻底改变了 UC 的护理，但仍有 10-25% 的患者药物治疗失败，但仍在进行手术。因此，开发新的治疗方法是 UC 的核心问题。T 细胞，尤其是 Th17 细胞，与 UC 密切相关，是 UC 药物治疗的主要靶点。组织驻留记忆 T 细胞 (TRM) 是一类独特的 T 细胞，在肠道中高度富集，与微生物群密切相关，并与 UC 的发病机制有关。与循环 T 细胞不同，TRM 难以靶向，因为它们不循环。因此，我们专注于像 IL-15 这样的细胞因子，它们充当组织危险信号并在原位调节 T 细胞。我们发现 IL-15 轴在 UC 中上调并预测治疗反应。IL-15 对于 Th17 分化是多余的，但可以激活终末分化的 Th17 细胞以促进肠道炎症。最后，在来自 UC 患者的 CD4+ TRM 中，IL-15 通过 Janus 激酶 (JAK)1 通路上调了 RORC，这是 Th17 细胞的主要转录因子。因此，IL-15 促进肠道中终末分化的炎性 Th17 细胞，增加了 IL-15 可能成为 UC 治疗靶标的可能性。