Activated Galectin-9/Tim3 promotes Treg and suppresses Th1 effector function in chronic lymphocytic leukemia
Activated Galectin-9/Tim3 promotes Treg and suppresses Th1 effector function in chronic lymphocytic leukemia
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活化的 Galectin-9/Tim3 在慢性淋巴细胞白血病中促进 Treg 并抑制 Th1 效应功能
DOI：
10.1096/fj.202100013r
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发表时间：
2021-07-01
期刊：
影响因子：
4.8
通讯作者：
Ding, Jianbing
中科院分区：
文献类型：
--
作者：
Pang, Nannan;Alimu, Xierenguli;Ding, Jianbing
TIM-3是一种负性免疫调节因子，但其在慢性淋巴细胞白血病(CLL)中的作用机制尚不清楚。本研究的目的是了解Galectin-9/Tim-3信号通路在CLL患者CD4(+)T细胞亚群调节中的作用。流式细胞仪检测结果显示，CLL患者Treg细胞数量明显增加，并存在明显的Treg/Th17失衡。此外，慢性淋巴细胞性白血病患者Th1和Treg细胞表面TIM-3高表达。慢性淋巴细胞性白血病患者血清Galectin-9和IL-10水平明显升高，尤其是B期和C期，而γ-干扰素水平下降。此外，CLL患者血清Galectin-9水平与TIM-3(+)Treg细胞数量及IL-10水平呈正相关。有趣的是，当TIM-3/Galectin-9途径在体外被阻断时，CD4(+)T细胞培养上清液中IL-10的水平显著降低，而干扰素-γ和肿瘤坏死因子-α的水平显著升高。与活化的Th1细胞共培养后，CLL细胞的凋亡率显著增加，经Tim-3(+)Tregs处理后，这种作用被逆转。总之，Galectin-9/Tim-3在慢性淋巴细胞性白血病中升高，并与疾病进展有关。激活的Galectin-9/Tim-3通过对CD4(+)T细胞的负性调节，抑制Th1效应功能，并促进Treg参与CLL的免疫逃逸。该通路可能成为CLL患者免疫治疗的潜在靶点。
Tim-3 is a negative immunoregulator in anti-tumor response, but its mechanism in chronic lymphocytic leukemia (CLL) is not yet clear. The aim of this study was to understand the role of Galectin-9/Tim-3 signaling pathway in the regulation of CD4(+) T cell subsets in CLL patients. Flow cytometry results showed that the number of Treg cells obviously increased, and there was a significant Treg/Th17 imbalance in CLL patients. In addition, Tim-3 overexpressed on the surface of Th1 and Treg cells in CLL patients. The levels of Galectin-9 and IL-10 were significantly elevated in patients of CLL, especially in stages of Binet B, and C. However, IFN-gamma decreased. Moreover, Galectin-9 in CLL patients was positively correlated with the number of Tim-3(+) Treg cells and the level of IL-10. Interestingly, when the Tim-3/Galectin-9 pathway was blocked in vitro, the level of IL-10 in the culture supernatant of CD4(+) T was significantly reduced, while the levels of IFN-gamma and TNF-alpha were increased. After co-culture with activated Th1 cells, the apoptosis of CLL cells was significantly increased, and this effect was reversed after treatment with Tim-3(+) Tregs. In summary, Galectin-9/Tim-3 are elevated in CLL and associated with disease progression. By the negative regulation of CD4(+) T cells, activated Galectin-9/Tim-3 suppresses Th1 effector function and also promotes Treg to be involved in immune escape of CLL. This pathway might become the potential target of immunotherapy in CLL patients.