白细胞介素 17 (IL-17) 家族细胞因子促进保护性炎症以抵抗病原体，同时也促进自身免疫和肿瘤发展。 IL-17 向调节性 T 细胞 (Treg) 发出的直接信号尚未报道，可能有助于解释这些二分反应。我们通过将 Foxp3-YFP-Cre 小鼠与 Il17ra-flox 小鼠 (Il17ra) 杂交，在 Tregs 中条件性敲除 Il17ra ΔTreg 小鼠）。随后，我们将 Il17ra ΔTreg 小鼠的骨髓细胞过继转移至散发性结直肠癌小鼠模型 (Cdx2-Cre /Apc F/ )，以选择性消除结直肠癌中 Tregs 上的 IL-17 直接信号传导。对小鼠结直肠肿瘤的纯化 Treg 进行单细胞 RNA 测序和批量 RNA 测序，并与人类肿瘤浸润 Treg 细胞进行比较。IL-17 受体 A (IL-17RA) 在小鼠肠系膜淋巴结中的 Tregs 中表达和结肠肿瘤。 IL-17RA 的消除，特别是 Tregs 中的 IL-17RA 的消除，导致 Th17 细胞增加，并加剧肿瘤的发展。从机制上讲，肿瘤浸润性 Tregs 表现出独特的基因特征，与其激活、成熟和抑制功能相关，并且这种特征在一定程度上得到 IL-17 向 Tregs 的直接信号传导的支持。为了研究 Treg 编程途径，我们发现肿瘤 Tregs 中 IL-17RA 的缺失导致 RNA 剪接减少，以及已知调节选择性剪接和促进 Treg 功能的几种 RNA 结合蛋白的下调。IL-17 直接向 Tregs 发出信号并促进其成熟和功能。该信号通路构成了一个负反馈环，控制 CRC 中促癌炎症。版权所有 © 2024 Theune、Chen、Theune、Ye、Ménoret、Vella 和 Wang。

Interleukin-17 (IL-17) family cytokines promote protective inflammation for pathogen resistance, but also facilitate autoimmunity and tumor development. A direct signal of IL-17 to regulatory T cells (Tregs) has not been reported and may help explain these dichotomous responses.We generated a conditional knockout of Il17ra in Tregs by crossing Foxp3-YFP-Cre mice to Il17ra-flox mice (Il17ra ΔTreg mice). Subsequently, we adoptively transferred bone marrow cells from Il17ra ΔTreg mice to a mouse model of sporadic colorectal cancer (Cdx2-Cre +/Apc F/+), to selectively ablate IL-17 direct signaling on Tregs in colorectal cancer. Single cell RNA sequencing and bulk RNA sequencing were performed on purified Tregs from mouse colorectal tumors, and compared to those of human tumor infiltrating Treg cells.IL-17 Receptor A (IL-17RA) is expressed in Tregs that reside in mouse mesenteric lymph nodes and colon tumors. Ablation of IL-17RA, specifically in Tregs, resulted in increased Th17 cells, and exacerbated tumor development. Mechanistically, tumor-infiltrating Tregs exhibit a unique gene signature that is linked to their activation, maturation, and suppression function, and this signature is in part supported by the direct signaling of IL-17 to Tregs. To study pathways of Treg programming, we found that loss of IL-17RA in tumor Tregs resulted in reduced RNA splicing, and downregulation of several RNA binding proteins that are known to regulate alternative splicing and promote Treg function.IL-17 directly signals to Tregs and promotes their maturation and function. This signaling pathway constitutes a negative feedback loop that controls cancer-promoting inflammation in CRC.Copyright © 2024 Theune, Chen, Theune, Ye, Ménoret, Vella and Wang.