Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China.
Department of Rheumatology and Immunology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Front Immunol. 2022 Jul 7;13:922307. doi: 10.3389/fimmu.2022.922307. eCollection 2022.
This study aimed to elucidate the changes and associated mechanisms of circulating CD28- cytotoxic T lymphocytes (CTLs) in patients with IgG4-related disease (IgG4-RD).
Fifty IgG4-RD patients and 15 healthy controls (HCs) were recruited. Peripheral blood mononuclear cells (PBMCs) were isolated, the levels of circulating CD28- CTLs were detected by flow cytometry, and the proportions of CD127lo or GZMB+CD28- CTL subsets were analyzed in the meantime. Mechanistically, PBMCs isolated from IgG4-RD patients were stimulated with IL-7 in the presence or absence of the JAK inhibitor tofacitinib. Flow cytometry was used to analyze the proliferation of CD28- CTLs and the changes in related subpopulations.
Circulating CD4+CD28- CTLs and CD8+CD28- CTLs were significantly increased in IgG4-RD patients compared with HCs, accompanied by an elevation of CD127lo or GZMB+ CTL subsets. The culture of PBMCs showed that IL-7 could induce the amplification of CD4+CD28- CTLs and CD8+CD28- CTLs in IgG4-RD. Furthermore, IL-7 promotes the proliferation and functional subset changes of these CD28- CTLs in this disease. The selective JAK inhibitor tofacitinib significantly inhibited the effects of IL-7 on CD4+CD28- CTLs and CD8+CD28- CTLs.
IL-7 can affect the immune balance of IgG4-RD patients by promoting the expansion and function of CD4+CD28- and CD8+CD28- CTLs in IgG4-RD through the JAK pathway. Blockade of the IL-7 signaling pathway may be a new therapeutic strategy for IgG4-RD.
本研究旨在阐明 IgG4 相关疾病（IgG4-RD）患者循环 CD28-细胞毒性 T 淋巴细胞（CTLs）的变化及其相关机制。
招募了 50 例 IgG4-RD 患者和 15 名健康对照者（HCs）。分离外周血单个核细胞（PBMCs），通过流式细胞术检测循环 CD28-CTLs 的水平，同时分析 CD127lo 或 GZMB+CD28-CTL 亚群的比例。从 IgG4-RD 患者中分离出的 PBMCs 在存在或不存在 JAK 抑制剂托法替尼的情况下，用 IL-7 刺激，通过流式细胞术分析 CD28-CTLs 的增殖和相关亚群的变化。
与 HCs 相比，IgG4-RD 患者的循环 CD4+CD28-CTLs 和 CD8+CD28-CTLs 明显增加，同时伴有 CD127lo 或 GZMB+CTL 亚群的升高。PBMCs 的培养表明，IL-7 可以诱导 IgG4-RD 中 CD4+CD28-CTLs 和 CD8+CD28-CTLs 的扩增。此外，IL-7 促进了这些 CD28-CTLs 在该疾病中的增殖和功能亚群的变化。选择性 JAK 抑制剂托法替尼显著抑制了 IL-7 对 CD4+CD28-CTLs 和 CD8+CD28-CTLs 的作用。
IL-7 通过 JAK 途径促进 IgG4-RD 中 CD4+CD28-和 CD8+CD28-CTLs 的扩增和功能，影响 IgG4-RD 患者的免疫平衡。阻断 IL-7 信号通路可能是 IgG4-RD 的一种新的治疗策略。
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