Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
Department of Respiratory and Critical Care Medicine, Wuming Hospital of Guangxi Medical University, Nanning, Guangxi, China.
Immunology. 2024 Sep;173(1):152-171. doi: 10.1111/imm.13820. Epub 2024 Jun 3.
Overexpression of T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) on T cells has been observed in smokers. However, whether and how galectin-9 (Gal-9)/TIM-3 signal between T-regulatory cells (Tregs) and type 17 helper (Th17) cells contributes to tobacco smoke-induced airway inflammation remains unclear. Here, we aimed to explore the role of the Gal-9/TIM-3 signal between Tregs and Th17 cells during chronic tobacco smoke exposure. Tregs phenotype and the expression of TIM-3 on CD4 T cells were detected in a mouse model of experimental emphysema. The role of TIM-3 in CD4 T cells was explored in a HAVCR2 mouse model and in mice that received recombinant anti-TIM3. The crosstalk between Gal-9 and Tim-3 was evaluated by coculture Tregs with effector CD4 T cells. We also invested the expression of Gal-9 in Tregs in patients with COPD. Our study revealed that chronic tobacco smoke exposure significantly reduces the frequency of Tregs in the lungs of mice and remarkably shapes the heterogeneity of Tregs by downregulating the expression of Gal-9. We observed a pro-inflammatory but restrained phenotypic transition of CD4 T cells after tobacco smoke exposure, which was maintained by TIM-3. The restrained phenotype of CD4 T cells was perturbed when TIM-3 was deleted or neutralised. Tregs from the lungs of mice with emphysema displayed a blunt ability to inhibit the differentiation and proliferation of Th17 cells. The inhibitory function of Tregs was partially restored by using recombinant Gal-9. The interaction between Gal-9 and TIM-3 inhibits the differentiation of Th17 cells and promotes apoptosis of CD4 T cells, possibly by interfering with the expression of retinoic acid receptor-related orphan receptor gamma t. The expression of Gal-9 in Tregs was reduced in patients with COPD, which was associated with Th17 response and lung function. These findings present a new paradigm that impairment of Gal-9/Tim-3 crosstalk between Tregs and Th17 cells during chronic tobacco smoke exposure promotes tobacco smoke-induced airway/lung inflammation.
T 细胞中 T 细胞免疫球蛋白和粘蛋白结构域 3（TIM-3）的过度表达已在吸烟者中观察到。然而，Galectin-9（Gal-9）/TIM-3 信号在调节性 T 细胞（Tregs）和 17 型辅助（Th17）细胞之间是否以及如何有助于烟草烟雾引起的气道炎症尚不清楚。在这里，我们旨在探讨 Gal-9/TIM-3 信号在 Tregs 和 Th17 细胞之间在慢性烟草烟雾暴露期间的作用。在实验性肺气肿小鼠模型中检测 T regs 表型和 CD4 T 细胞上 TIM-3 的表达。在 HAVCR2 小鼠模型和接受重组抗 TIM3 的小鼠中探索了 TIM-3 在 CD4 T 细胞中的作用。通过共培养 Tregs 和效应性 CD4 T 细胞来评估 Gal-9 和 Tim-3 之间的串扰。我们还研究了 COPD 患者中 Tregs 中 Gal-9 的表达。我们的研究表明，慢性烟草烟雾暴露显著降低了小鼠肺部 Tregs 的频率，并通过下调 Gal-9 的表达显著塑造了 Tregs 的异质性。我们观察到烟草烟雾暴露后 CD4 T 细胞发生了促炎但受抑制的表型转变，这一转变由 TIM-3 维持。当 TIM-3 缺失或中和时，CD4 T 细胞的受抑制表型受到干扰。肺气肿小鼠肺部的 Tregs 显示出抑制 Th17 细胞分化和增殖的能力减弱。使用重组 Gal-9 部分恢复了 Tregs 的抑制功能。Gal-9 和 TIM-3 之间的相互作用抑制了 Th17 细胞的分化，并促进了 CD4 T 细胞的凋亡，可能是通过干扰视黄酸受体相关孤儿受体γ t 的表达。COPD 患者中 Tregs 的 Gal-9 表达减少，这与 Th17 反应和肺功能有关。这些发现提出了一个新的范例，即在慢性烟草烟雾暴露期间 Tregs 和 Th17 细胞之间 Gal-9/Tim-3 串扰的损害促进了烟草烟雾引起的气道/肺炎症。
