University of Occupational and Environmental Health, Kitakyushu, Japan, and The Fourth Hospital of Hebei Medical University, Hebei, China.
University of Occupational and Environmental Health, Kitakyushu, Japan.
Arthritis Rheumatol. 2021 Jan;73(1):132-142. doi: 10.1002/art.41457. Epub 2020 Nov 10.
This study was undertaken to identify characteristics of follicular regulatory T (Tfr) cells and elucidate the mechanisms by which follicular helper T (Tfh) cells convert to Tfr cells. We probed the phenotype of T helper cells in patients with systemic lupus erythematosus (SLE) and underlying transcriptional regulation using cytokine-induced STAT family factors.
Peripheral blood mononuclear cells from 41 patients with SLE and 26 healthy donors were used to sort out the memory Tfh cell subset, and Tfh cells were cultured under various conditions. The phenotype of T helper cells and underlying mechanisms of transcriptional regulation were probed using flow cytometry and quantitative polymerase chain reaction analyses. These analyses evaluated the expression of characteristic markers and phosphorylation of STATs. Chromatin immunoprecipitation was used to evaluate histone modifications.
In patients with SLE, the proportion of CD4+CXCR5+FoxP3-PD-1 Tfh cells was increased (P < 0.01), whereas the proportion of CD4+CXCR5+CD45RA-FoxP3 activated Tfr cells was decreased (P < 0.05). Serum interleukin-2 (IL-2) levels were also reduced in patients with SLE. IL-2 induced conversion of memory Tfh cells to functional Tfr cells, which was characterized by CXCR5+Bcl-6+FoxP3 pSTAT3+pSTAT5+ cells. The loci of FOXP3 and BCL6 at STAT binding sites were marked by bivalent histone modifications. Following IL-2 stimulation, STAT3 and STAT5 selectively bound to FOXP3 and BCL6 gene loci accompanied by suppression of H3K27me3. Finally, IL-2 stimulation suppressed the generation of CD38+CD27 plasmablasts in Tfh and B cell coculture assays ex vivo.
Impaired function of Tfr cells might be attributed to defective IL-2 production. Exogenous IL-2 restores the function of Tfr cells through the conversion of Tfh cells to Tfr cells in patients with SLE. Thus, restoring balance between Tfh and Tfr cells may provide new therapeutic approaches in SLE.
本研究旨在鉴定滤泡调节性 T（Tfr）细胞的特征，并阐明滤泡辅助性 T（Tfh）细胞向 Tfr 细胞转化的机制。我们使用细胞因子诱导的 STAT 家族因子探测系统性红斑狼疮（SLE）患者辅助性 T 细胞的表型及其潜在的转录调控。
使用来自 41 例 SLE 患者和 26 例健康供体的外周血单个核细胞分选记忆性 Tfh 细胞亚群，并在不同条件下培养 Tfh 细胞。使用流式细胞术和定量聚合酶链反应分析探测辅助性 T 细胞的表型和潜在的转录调控机制。这些分析评估了特征性标记物的表达和 STAT 的磷酸化。染色质免疫沉淀用于评估组蛋白修饰。
SLE 患者中，CD4+CXCR5+FoxP3-PD-1 Tfh 细胞的比例增加（P<0.01），而 CD4+CXCR5+CD45RA-FoxP3 激活的 Tfr 细胞的比例降低（P<0.05）。SLE 患者的血清白细胞介素-2（IL-2）水平也降低。IL-2 诱导记忆性 Tfh 细胞向功能性 Tfr 细胞转化，其特征为 CXCR5+Bcl-6+FoxP3 pSTAT3+pSTAT5+细胞。FOXP3 和 BCL6 基因座上的 STAT 结合位点被双价组蛋白修饰标记。在 IL-2 刺激后，STAT3 和 STAT5 选择性地结合到 FOXP3 和 BCL6 基因座上，同时抑制 H3K27me3。最后，在体外 Tfh 和 B 细胞共培养实验中，IL-2 刺激抑制了 CD38+CD27 浆母细胞的生成。
Tfr 细胞功能障碍可能归因于 IL-2 产生缺陷。外源性 IL-2 通过在 SLE 患者中诱导 Tfh 细胞向 Tfr 细胞转化来恢复 Tfr 细胞的功能。因此，恢复 Tfh 和 Tfr 细胞之间的平衡可能为 SLE 提供新的治疗方法。
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