Akiyama Mitsuhiro, Wakasugi Sohma, Yoshimoto Keiko, Saito Koichi, Ishigaki Sho, Inukai Risa, Matsuno Yoshiyuki, Alshehri Waleed, Kondo Yasushi, Kaneko Yuko
Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan.
Inflamm Regen. 2025 Feb 6;45(1):4. doi: 10.1186/s41232-025-00367-4.
Recent evidence suggests that clonally expanded cytotoxic T cells play a role in various autoimmune diseases. Late-onset rheumatoid arthritis (LORA) exhibits unique characteristics compared to other RA forms, suggesting distinct immunological mechanisms. This study aimed to examine the involvement of cytotoxic T cells in LORA.
Fresh peripheral blood samples were collected from 78 treatment-naïve active RA patients, 12 with difficult-to-treat RA, and 16 healthy controls. Flow cytometry was employed to measure the proportions of CX3CR1cytotoxic CD4 and CD8 T cells in these samples. Additionally, immunohistochemical staining was performed on lymphoid node and synovial biopsy samples from patients with RA.
CX3CR1cytotoxic CD4 T cells were specifically increased in untreated, active patients with LORA, displaying features of CXCR3 age-associated T helper cells known as "ThA". CX3CR1⁺CD4⁺ T cells were identified as a cytotoxic ThA subset, as nearly all of these cells specifically expressed granzyme B. These cells were observed in enlarged lymph nodes and were found to infiltrate synovial tissues from patients with LORA. The proportions of CX3CR1CD4 T cells positively correlated with arthritis activity in LORA. The number of cells decreased after treatment with methotrexate, tumor necrosis factor inhibitors, and interleukin-6 inhibitors, whereas T-cell activation modulators did not affect them. Moreover, PD-1CD38CX3CR1CD4 T cells were identified as a treatment-resistant T cell subset that was characteristically increased in difficult-to-treat RA. CX3CR1CD8 T cells showed no significant difference between RA patients and healthy individuals, and no correlation with disease activity was observed. However, a correlation with age was observed in RA patients.
Our findings suggest that the immunopathogenesis of RA differs by age of onset, with CX3CR1 age-associated cytotoxic CD4 T cells playing a significant role in LORA. Additionally, the presence of a specific CX3CR1 T cell subset may be linked to treatment resistance.
近期证据表明，克隆扩增的细胞毒性T细胞在多种自身免疫性疾病中起作用。与其他类风湿关节炎（RA）类型相比，迟发性类风湿关节炎（LORA）具有独特的特征，提示其免疫机制不同。本研究旨在探讨细胞毒性T细胞在LORA中的作用。
采集78例未经治疗的活动性RA患者、12例难治性RA患者及16例健康对照者的新鲜外周血样本。采用流式细胞术检测这些样本中CX3CR1⁺细胞毒性CD4和CD8 T细胞的比例。此外，对RA患者的淋巴结和滑膜活检样本进行免疫组化染色。
未经治疗的活动性LORA患者中，CX3CR1⁺细胞毒性CD4 T细胞特异性增加，表现出CXCR3年龄相关T辅助细胞（称为“ThA”）的特征。CX3CR1⁺CD4⁺ T细胞被鉴定为细胞毒性ThA亚群，因为几乎所有这些细胞都特异性表达颗粒酶B。这些细胞在肿大的淋巴结中被观察到，并发现其浸润LORA患者的滑膜组织。CX3CR1⁺CD4 T细胞的比例与LORA中的关节炎活动度呈正相关。用甲氨蝶呤、肿瘤坏死因子抑制剂和白细胞介素-6抑制剂治疗后细胞数量减少，而T细胞激活调节剂对其无影响。此外，PD-1⁺CD38⁺CX3CR1⁺CD4 T细胞被鉴定为对治疗耐药的T细胞亚群，在难治性RA中特征性增加。CX3CR1⁺CD8 T细胞在RA患者和健康个体之间无显著差异，且未观察到与疾病活动度的相关性。然而，在RA患者中观察到与年龄的相关性。
我们的研究结果表明，RA的免疫发病机制因发病年龄而异，CX3CR1年龄相关的细胞毒性CD4 T细胞在LORA中起重要作用。此外，特定CX3CR1 T细胞亚群的存在可能与治疗耐药性有关。
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