Clinical Medical Research Center for Obstetrics and Gynecology Diseases of Fujian Province, Laboratory of Research and Diagnosis of Gynecological Diseases of Xiamen City, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
School of Medicine, Xiamen University, Xiamen, China.
Immunology. 2024 Jul;172(3):469-485. doi: 10.1111/imm.13786. Epub 2024 Mar 27.
Endometriosis is defined as an oestrogen-dependent and inflammatory gynaecological disease of which the pathogenesis remains unclear. This study aimed to investigate the cellular heterogeneity and reveal the effect of CD8 T cells on the progress of endometriosis. Three ovarian endometriosis patients were collected, and single-cell RNA sequencing (scRNA-seq) progressed and delineated the cellular landscape of endometriosis containing five cell clusters. The endometrial cells (EMCs) were the major component, of which the mesenchymal cells were preponderant and characterized with increased inflammation and oestrogen synthesis in endometriosis. The proportion of T cells, mainly CD8 T cells rather than CD4, was reduced in endometriotic lesions, and the cytokines and cytotoxicity of ectopic T cells were depressed. CD8 T cells depressed the proliferation of ESCs through inhibiting CDK1/CCNB1 pathway to arrest the cell cycle and triggered inflammation through activating STAT1 pathway. Correspondingly, the coculture with ESCs resulted in the dysfunction of CD8 T cells through upregulating STAT1/PDCD1 pathway and glycolysis-promoted metabolism reprogramming. The endometriotic lesions were larger in nude mouse models with T-cell deficiency than the normal mouse models. The inhibition of T cells via CD90.2 or CD8A antibody increased the endometriotic lesions in mouse models, and the supplement of T cells to nude mouse models diminished the lesion sizes. In conclusion, this study revealed the global cellular variation of endometriosis among which the cellular count and physiology of EMCs and T cells were significantly changed. The depressed cytotoxicity and aberrant metabolism of CD8 T cells were induced by ESCs with the activation of STAT1/PDCD1 pathway resulting in immune survival to promote endometriosis.
子宫内膜异位症是一种雌激素依赖性和炎症性妇科疾病，其发病机制尚不清楚。本研究旨在探讨细胞异质性，并揭示 CD8 T 细胞对子宫内膜异位症进展的影响。收集了 3 名卵巢子宫内膜异位症患者，进行单细胞 RNA 测序 (scRNA-seq)，并描绘了包含 5 个细胞簇的子宫内膜异位症细胞景观。子宫内膜细胞 (EMCs) 是主要成分，其中间充质细胞占优势，并表现出子宫内膜异位症中炎症和雌激素合成增加。子宫内膜异位症病灶中 T 细胞，主要是 CD8 T 细胞而不是 CD4 T 细胞的比例减少，异位 T 细胞的细胞因子和细胞毒性受到抑制。CD8 T 细胞通过抑制 CDK1/CCNB1 通路抑制 ESCs 的增殖，从而阻断细胞周期，并通过激活 STAT1 通路引发炎症。相应地，与 ESCs 的共培养通过上调 STAT1/PDCD1 通路和糖酵解促进的代谢重编程导致 CD8 T 细胞功能障碍。与正常小鼠模型相比，T 细胞缺陷型裸鼠模型中的子宫内膜异位症病灶更大。通过 CD90.2 或 CD8A 抗体抑制 T 细胞会增加小鼠模型中的子宫内膜异位症病灶，而向裸鼠模型补充 T 细胞会减少病灶大小。总之，本研究揭示了子宫内膜异位症的全局细胞变化，其中 EMCs 和 T 细胞的细胞计数和生理学发生了显著变化。ESCs 通过激活 STAT1/PDCD1 通路诱导 CD8 T 细胞的细胞毒性降低和代谢异常，从而产生免疫逃避，促进子宫内膜异位症的发生。
