Guangxi Medical University, Nanning, China.
The Second Affiliated Hospital of Guangxi Medical University, Nanning, China.
Front Immunol. 2024 Nov 1;15:1482213. doi: 10.3389/fimmu.2024.1482213. eCollection 2024.
IFN-γ+CD4+ cells (type 1 helper T cells, Th1) represent a critical component of the inflammatory environment in the lungs of chronic obstructive pulmonary disease (COPD). Identifying influencing factors related to COPD-associated Th1 cells will enhance our understanding of the inflammatory mechanisms involved and facilitate the development of targeted interventions.
We describe T-cell immunoglobulin and mucin-domain containing-3 (Tim3) as a key gene regulating COPD-associated Th1 cells through single-cell sequencing, flow cytometry and knockout mice.
Our findings indicate that Havcr2 expression gradually increases during CD4+ T cell activation in COPD mice, with Tim3 being highly expressed on both CD4+ T cells and Th1 cells. Notably, the knockout of HAVCR2 further promotes the infiltration of CD4+ T cells and the expression of IFN-γ in the lungs, resulting in a more severe emphysema phenotype, although it does not significantly affect TNF-α expression. Additionally, NFIL3, an upstream regulator of Tim3, is also highly expressed in the CD4+ T cells of COPD mice. Mice with NFIL3 knockout exhibit phenotypes similar to those of HAVCR2 knockout mice, along with a significant downregulation of Tim3 expression. , we simulated the activation process by polarizing primary CD4+ Tn cells from COPD mice and observed that NFIL3/Tim3 expression was significantly upregulated following Th1 polarization.
Our study demonstrates that the NFIL3/Tim3 axis plays a role in Th1 imbalance in the lungs of COPD by inhibiting Th1 differentiation.
IFN-γ+CD4+细胞（1 型辅助性 T 细胞，Th1）是慢性阻塞性肺疾病（COPD）肺部炎症环境的关键组成部分。确定与 COPD 相关 Th1 细胞相关的影响因素将增强我们对炎症机制的理解，并有助于开发靶向干预措施。
我们通过单细胞测序、流式细胞术和基因敲除小鼠描述了 T 细胞免疫球蛋白和粘蛋白结构域包含蛋白 3（Tim3）作为调节 COPD 相关 Th1 细胞的关键基因。
我们的研究结果表明，在 COPD 小鼠的 CD4+T 细胞激活过程中，Havcr2 的表达逐渐增加，Tim3 在 CD4+T 细胞和 Th1 细胞上均高度表达。值得注意的是，HAVCR2 的敲除进一步促进了 CD4+T 细胞在肺部的浸润和 IFN-γ的表达，导致更严重的肺气肿表型，尽管它对 TNF-α的表达没有显著影响。此外，Tim3 的上游调节因子 NFIL3 在 COPD 小鼠的 CD4+T 细胞中也高度表达。NFIL3 基因敲除的小鼠表现出与 HAVCR2 基因敲除小鼠相似的表型，同时 Tim3 的表达显著下调。此外，我们通过极化 COPD 小鼠的原代 CD4+Tn 细胞模拟激活过程，观察到 NFIL3/Tim3 表达在 Th1 极化后显著上调。
我们的研究表明，NFIL3/Tim3 轴通过抑制 Th1 分化在 COPD 肺部的 Th1 失衡中发挥作用。
