Hematology Department, Tianjin Medical University General Hospital, Tianjin, China.
Emergency Department, Tianjin Medical University General Hospital, Tianjin, China.
J Cell Mol Med. 2020 Jan;24(1):1046-1058. doi: 10.1111/jcmm.14825. Epub 2019 Nov 22.
CD8 T cells play a central role in antitumour immunity, which often exhibit 'exhaustion' in the setting of malignancy and chronic viral infection due to T cell immunoglobulin and mucin domain 3 (TIM3) and myeloid-derived suppressor cells (MDSCs). Our team previously found that overactive MDSCs and exhausted TIM3 CD8 T cells were observed in myelodysplastic syndromes (MDS) patients. However, it is not obvious whether MDSCs suppress CD8 T cells through TIM3/Gal-9 pathway. Here, Gal-9, as the ligand of TIM3, was overexpressed in MDSCs. The levels of Gal-9 in bone marrow supernatants, serum and culture supernatants of MDSCs from MDS patients were elevated. CD8 T cells from MDS or normal controls produced less perforin and granzyme B and exhibited increased early apoptosis after co-culture with MDSCs from MDS. Meanwhile, the cytokines produced by CD8 T cells could be partially restored by TIM3/Gal-9 pathway inhibitors. Furthermore, CD8 T cells produced less perforin and granzyme B after co-culture with excess exogenous Gal-9, and the function of CD8 T cells was similarly restored by TIM3/Gal-9 pathway inhibitors. Expression of Notch1, EOMES (associated with perforin and granzyme B secretion), p-mTOR and p-AKT (associated with cell proliferation) was decreased in CD8 T cells from MDS after co-culture with excess exogenous Gal-9. These suggested that MDSCs might be the donor of Gal-9, and TIM3/Gal-9 pathway might be involved in CD8 T cells exhaustion in MDS, and that TIM3/Gal-9 pathway inhibitor might be the promising candidate for target therapy of MDS in the future.
CD8 T 细胞在抗肿瘤免疫中发挥核心作用，但在恶性肿瘤和慢性病毒感染的情况下，由于 T 细胞免疫球蛋白和粘蛋白结构域 3（TIM3）和髓系来源的抑制细胞（MDSC）的存在，这些细胞往往会出现“衰竭”。我们的团队之前发现，骨髓增生异常综合征（MDS）患者中存在过度活跃的 MDSC 和衰竭的 TIM3 CD8 T 细胞。然而，MDSC 是否通过 TIM3/Gal-9 途径抑制 CD8 T 细胞尚不清楚。在这里，Gal-9 作为 TIM3 的配体，在 MDSC 中过表达。MDS 患者骨髓上清液、血清和 MDSC 培养上清液中 Gal-9 水平升高。MDS 或正常对照 CD8 T 细胞与 MDSC 共培养后，穿孔素和颗粒酶 B 的产生减少，早期凋亡增加。同时，CD8 T 细胞产生的细胞因子可部分通过 TIM3/Gal-9 途径抑制剂恢复。此外，与过量外源性 Gal-9 共培养后，CD8 T 细胞产生的穿孔素和颗粒酶 B 减少，CD8 T 细胞的功能也可通过 TIM3/Gal-9 途径抑制剂得到类似恢复。与过量外源性 Gal-9 共培养后，MDS CD8 T 细胞中 Notch1、EOMES（与穿孔素和颗粒酶 B 分泌相关）、p-mTOR 和 p-AKT（与细胞增殖相关）的表达降低。这些表明 MDSC 可能是 Gal-9 的供体，TIM3/Gal-9 途径可能参与 MDS 中 CD8 T 细胞衰竭，TIM3/Gal-9 途径抑制剂可能是 MDS 未来靶向治疗的有希望的候选药物。
