■白细胞介素-17(IL-17)家族细胞因子促进保护性炎症抵抗病原体,而且还促进自身免疫和肿瘤的发展。IL-17对调节性T细胞(Tregs)的直接信号尚未报道,可能有助于解释这些二分法反应。
■我们通过将Foxp3-YFP-Cre小鼠与Il17ra-flox小鼠(Il17raΔTreg小鼠)杂交,在Treg中产生了Il17ra的条件性敲除。随后,我们将Il17raΔTreg小鼠的骨髓细胞过继转移到散发性结直肠癌的小鼠模型(Cdx2-Cre/ApcF/),在结直肠癌中选择性消融IL-17对Tregs的直接信号传导。对来自小鼠结肠直肠肿瘤的纯化Treg进行单细胞RNA测序和批量RNA测序,并与人类肿瘤浸润的Treg细胞进行比较。
IL-17受体A(IL-17RA)在存在于小鼠肠系膜淋巴结和结肠肿瘤中的Treg中表达。IL-17RA消融,特别是在Tregs中,导致Th17细胞增加,并加剧了肿瘤的发展。机械上,肿瘤浸润性Tregs表现出与其激活相关的独特基因特征,成熟,和抑制函数,并且该签名部分由IL-17向Tregs的直接信号传导支持。为了研究Treg编程的途径,我们发现肿瘤Tregs中IL-17RA的缺失导致RNA剪接减少,和下调几种RNA结合蛋白,已知这些蛋白可以调节可变剪接并促进Treg功能。
■IL-17直接向Tregs发出信号,并促进其成熟和功能。该信号传导途径构成了一个负反馈回路,可控制CRC中的促癌炎症。
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.