LAG3和TIM3的共表达可识别出一种有效的调节性T细胞群体，该群体可抑制结直肠癌患者巨噬细胞的功能。
Co-expression of LAG3 and TIM3 identifies a potent Treg population that suppresses macrophage functions in colorectal cancer patients.
作者信息
Ma Qiang, Liu Junning, Wu Guoliang, Teng Mujian, Wang Shaoxuan, Cui Meng, Li Yuantao
机构信息
Department of Surgery, Shandong Qianfoshan Hospital, Shandong University, Jinan, Shandong, China.
Department of Gastroenterology, Jining First People's Hospital, Jining, Shandong, China.
出版信息
Clin Exp Pharmacol Physiol. 2018 Oct;45(10):1002-1009. doi: 10.1111/1440-1681.12992. Epub 2018 Jul 26.
Regulatory T (Treg) cells are critical suppressors of inflammation and are thought to exert mainly deleterious effects in cancers. In colorectal cancer (CRC), Foxp3 Treg accumulation in tumors was associated with poor prognosis. Hence, we examined the circulating Treg cells in CRC patients. Compared to controls, CRC patients presented mild upregulations in CD4 CD25 T cells and in the more canonical CD4 CD25 Foxp3 Treg cells in peripheral blood mononuclear cells. Both of these Treg populations could be roughly divided into lymphocyte activation gene 3 negative T cell immunoglobulin and mucin-domain containing-3 negative (LAG3 TIM3 ) and LAG3 TIM3 subsets. In CRC patients, the LAG3 TIM3 subset represented approximately half of CD4 CD25 T cells and greater than 60% of CD4 CD25 Foxp3 Treg cells, which was significantly more frequent than in healthy controls. Compared to the LAG3 TIM3 CD4 CD25 T cells, the LAG3 TIM3 CD4 CD25 T cells presented considerably higher transforming growth factor-β and slightly higher interleukin (IL)-10 secretion, together with higher cytotoxic T-lymphocyte associated protein 4 and Foxp3 expression levels. Notably, macrophages following incubation with LAG3 TIM3 CD4 CD25 T cells and LAG3 TIM3 CD4 CD25 T cells displayed different characteristics. Macrophages incubated with LAG3 TIM3 CD4 CD25 T cells presented lower expression of major histocompatibility complex class II, CD80, CD86, and tumor necrosis factor-α but higher expression of IL-10, than macrophages incubated with LAG3 TIM3 CD4 CD25 T cells. Together, our investigations demonstrated that CRC patients presented an enrichment of circulating Treg cells, in which the LAG3 TIM3 subset exhibited more potent expression of inhibitory molecules, and furthermore, the LAG3 TIM3 Treg cells could suppress the proinflammatory activation of macrophages more potently than the LAG3 TIM3 Treg cells.
调节性T（Treg）细胞是炎症的关键抑制因子，被认为在癌症中主要发挥有害作用。在结直肠癌（CRC）中，肿瘤内Foxp3 Treg细胞的积累与预后不良相关。因此，我们检测了CRC患者循环中的Treg细胞。与对照组相比，CRC患者外周血单个核细胞中CD4⁺CD25⁺ T细胞以及更典型的CD4⁺CD25⁺Foxp3⁺ Treg细胞出现轻度上调。这两种Treg细胞群大致可分为淋巴细胞激活基因3阴性T细胞免疫球蛋白和粘蛋白结构域包含分子3阴性（LAG3⁻TIM3⁻）和LAG3⁺TIM3⁺亚群。在CRC患者中，LAG3⁺TIM3⁺亚群约占CD4⁺CD25⁺ T细胞的一半，占CD4⁺CD25⁺Foxp3⁺ Treg细胞的60%以上，这一比例显著高于健康对照组。与LAG3⁻TIM3⁻ CD4⁺CD25⁺ T细胞相比LAG3⁺TIM3⁺ CD4⁺CD25⁺ T细胞表现出更高的转化生长因子-β分泌以及略高的白细胞介素（IL）-10分泌，同时细胞毒性T淋巴细胞相关蛋白4和Foxp3表达水平更高。值得注意的是，与LAG3⁺TIM3⁺ CD4⁺CD25⁺ T细胞和LAG3⁻TIM3⁻ CD4⁺CD25⁺ T细胞孵育后的巨噬细胞表现出不同的特征。与LAG3⁻TIM3⁻ CD4⁺CD25⁺ T细胞孵育的巨噬细胞相比，与LAG3⁺TIM3⁺ CD4⁺CD25⁺ T细胞孵育的巨噬细胞主要组织相容性复合体II类、CD8⁰、CD86和肿瘤坏死因子-α的表达较低，但IL-10的表达较高。总之，我们的研究表明CRC患者循环Treg细胞富集，其中LAG3⁺TIM3⁺亚群表现出更强的抑制分子表达，此外，LAG3⁺TIM3⁺ Treg细胞比LAG3⁻TIM3⁻ Treg细胞更有效地抑制巨噬细胞的促炎激活。
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