Impaired function of PD-1+ follicular regulatory T cells in systemic lupus erythematosus,Clinical & Experimental Immunology

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Impaired function of PD-1+ follicular regulatory T cells in systemic lupus erythematosus
Clinical & Experimental Immunology ( IF 3.4 ) Pub Date : 2021-07-09 , DOI: 10.1111/cei.13643
Izumi Kurata ₁ , Natsuko Mikami ₁ , Ayako Ohyama ₁ , Atsumu Osada ₁ , Yuya Kondo ₁ , Hiroto Tsuboi ₁ , Takayuki Sumida ₁ , Isao Matsumoto ₁

Affiliation

Aberrant autoantibody production is characteristic of systemic lupus erythematosus (SLE), but follicular regulatory T (TFR) cells can potentially suppress this abnormality. We investigate functional changes in TFR cells from SLE patients. Circulating TFR cells were collected from 19 SLE patients and 14 healthy controls (HC) to compare molecular expression and in-vitro suppressive capacity of follicular helper T (TFH) cell proliferation. To reveal the stability of forkhead box protein 3 (FoxP3) in TFR, pyrosequencing of conserved non-coding sequence (CNS) 2 at the FoxP3 gene locus was performed. We then tested interleukin (IL)-2 in SLE-TFR cells to check restoration of suppressor function. Programmed cell death 1 (PD-1) expression in SLE-TFR cells was positively correlated with anti-DNA antibody levels and disease activity. These cells had impaired suppressive function for TFH cells with decreased expression of suppression mediators FoxP3, cytotoxic T lymphocyte antigen 4 (CTLA-4) and IL-2 receptor alpha (IL-2Rα). Pyrosequencing identified hyper-methylation in CNS2 region of SLE-TFR cells comparing to HC. With in-vitro IL-2 stimulation, PD-1 expression of TFR cells significantly decreased, together with increased expression of FoxP3 and CTLA-4, especially at a low dose. Thus, SLE-TFR cells have functionally defective to TFH suppression, but low-dose IL-2 therapy might be useful to restore this ability.

中文翻译：

PD-1+滤泡调节性T细胞在系统性红斑狼疮中的功能受损

异常自身抗体产生是系统性红斑狼疮 (SLE) 的特征，但滤泡调节性 T (TFR) 细胞可能会抑制这种异常。我们研究了 SLE 患者 TFR 细胞的功能变化。从 19 名 SLE 患者和 14 名健康对照 (HC) 收集循环 TFR 细胞，以比较分子表达和体外滤泡辅助 T (TFH) 细胞增殖的抑制能力。为了揭示叉头盒蛋白 3 (FoxP3) 在 TFR 中的稳定性，对 FoxP3 基因位点的保守非编码序列 (CNS) 2 进行焦磷酸测序。然后我们在 SLE-TFR 细胞中测试了白细胞介素 (IL)-2 以检查抑制功能的恢复。SLE-TFR 细胞中的程序性细胞死亡 1 (PD-1) 表达与抗 DNA 抗体水平和疾病活动呈正相关。这些细胞对 TFH 细胞的抑制功能受损，抑制介质 FoxP3、细胞毒性 T 淋巴细胞抗原 4 (CTLA-4) 和 IL-2 受体α (IL-2Rα) 的表达降低。与 HC 相比，焦磷酸测序鉴定了 SLE-TFR 细胞的 CNS2 区域的高甲基化。与体外在 IL-2 刺激下，TFR 细胞的 PD-1 表达显着降低，同时 FoxP3 和 CTLA-4 的表达增加，尤其是在低剂量时。因此，SLE-TFR 细胞在抑制 TFH 方面存在功能缺陷，但低剂量 IL-2 治疗可能有助于恢复这种能力。

更新日期：2021-09-17

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