Laboratory of Endocrinology and Immune System, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
Cell Death Dis. 2023 Sep 21;14(9):618. doi: 10.1038/s41419-023-06146-8.
Immunosenescence and exhaustion are involved in the development and progression of type 2 diabetes (T2D) and metabolic liver diseases, including fatty liver, fibrosis, and cirrhosis, in humans. However, the relationships of the senescence and exhaustion of T cells with insulin resistance-associated liver diseases remain incompletely understood. To better define the relationship of T2D with nonalcoholic fatty liver disease, 59 patients (mean age 58.7 ± 11.0 years; 47.5% male) with T2D were studied. To characterize their systemic immunophenotypes, peripheral blood mononuclear cells were analyzed using flow cytometry. Magnetic resonance imaging (MRI)-based proton density fat fraction and MRI-based elastography were performed using an open-bore, vertical-field 3.0 T scanner to quantify liver fat and fibrosis, respectively. The participants with insulin resistance had a significantly larger population of CD28 - CD57+ senescent T cells among the CD4+ and CD8 + T cells than those with lower Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) values. The abundances of senescent CD4+ and CD8 + T cells and the HOMA-IR positively correlated with the severity of liver fibrosis, assessed using MRI-based elastography. Interleukin 15 from hepatic monocytes was found to be an inducer of bystander activation of T cells, which is associated with progression of liver disease in the participants with T2D. Furthermore, high expression of genes related to senescence and exhaustion was identified in CD4+ and CD8 + T cells from the participants with nonalcoholic steatohepatitis or liver cirrhosis. Finally, we have also demonstrated that hepatic T-cell senescence and exhaustion are induced in a diet or chemical-induced mouse model with nonalcoholic steatohepatitis. In conclusion, we have shown that T-cell senescence is associated with insulin resistance and metabolic liver disease in patients with T2D.
免疫衰老和衰竭与 2 型糖尿病（T2D）和代谢性肝病的发展和进展有关，包括脂肪肝、纤维化和肝硬化。然而，T 细胞衰老和衰竭与胰岛素抵抗相关肝病的关系仍不完全清楚。为了更好地定义 T2D 与非酒精性脂肪性肝病的关系，研究了 59 名 T2D 患者（平均年龄 58.7±11.0 岁；47.5%为男性）。为了描述他们的系统免疫表型，使用流式细胞术分析外周血单核细胞。使用开放式、垂直场 3.0T 扫描仪进行基于磁共振成像（MRI）的质子密度脂肪分数和基于 MRI 的弹性成像，以分别定量肝脂肪和纤维化。与胰岛素抵抗相关的参与者中，CD4+和 CD8+T 细胞中 CD28-CD57+衰老 T 细胞的比例明显高于 Homeostatic Model Assessment for Insulin Resistance（HOMA-IR）值较低的参与者。衰老的 CD4+和 CD8+T 细胞的丰度以及 HOMA-IR 与使用基于 MRI 的弹性成像评估的肝纤维化严重程度呈正相关。来自肝单核细胞的白细胞介素 15 被发现是 T 细胞旁观者激活的诱导剂，这与 T2D 患者肝病的进展有关。此外，还鉴定了非酒精性脂肪性肝炎或肝硬化患者的 CD4+和 CD8+T 细胞中与衰老和衰竭相关的基因表达较高。最后，我们还证明了在非酒精性脂肪性肝炎的饮食或化学诱导的小鼠模型中诱导了肝 T 细胞衰老和衰竭。总之，我们已经表明 T 细胞衰老与 T2D 患者的胰岛素抵抗和代谢性肝病有关。
