Yale University School of Medicine, New Haven, Connecticut.
Rutgers New Jersey Medical School, Newark.
Arthritis Rheumatol. 2021 Mar;73(3):478-489. doi: 10.1002/art.41532. Epub 2021 Jan 29.
To assess the role of STAT4 activation in driving pathogenic follicular helper T (Tfh) cell secretion of the cytokines interleukin-21 (IL-21) and interferon-γ (IFNγ) in murine and human lupus.
The effect of STAT4-dependent Tfh cell signaling on cytokine production and autoreactive B cell maturation was assessed temporally during the course of lupus in a murine model, with further assessment of Tfh cell gene transcription performed using RNA-Seq technology. STAT4-dependent signaling and cytokine production were also determined in circulating Tfh-like cells in patients with systemic lupus erythematosus (SLE), as compared to cells from healthy control subjects, and correlations with disease activity were assessed in the Tfh-like cells from SLE patients.
IL-21- and IFNγ-coproducing Tfh cells expanded prior to the detection of potentially pathogenic IgG2c autoantibodies in lupus-prone mice. Tfh cells transcriptionally evolved during the course of disease with acquisition of a STAT4-dependent gene signature. Maintenance of Tfh cell cytokine synthesis was dependent upon STAT4 signaling, driven by type I IFNs. Circulating Tfh-like cells from patients with SLE also secreted IL-21 and IFNγ, with STAT4 phosphorylation enhanced by IFNβ, in association with the extent of clinical disease activity.
We identified a role for type I IFN signaling in driving STAT4 activation and production of IL-21 and IFNγ by Tfh cells in murine and human lupus. Enhanced STAT4 activation in Tfh cells may underlie pathogenic B cell responses in both murine and human lupus. These data indicate that STAT4 guides pathogenic cytokine and immunoglobulin production in SLE, demonstrating a potential therapeutic target to modulate autoimmunity.
评估 STAT4 激活在驱动致病滤泡辅助 T（Tfh）细胞分泌细胞因子白细胞介素-21（IL-21）和干扰素-γ（IFNγ）在鼠和人类狼疮中的作用。
在狼疮小鼠模型中，评估 STAT4 依赖性 Tfh 细胞信号传导对细胞因子产生和自身反应性 B 细胞成熟的影响，同时使用 RNA-Seq 技术评估 Tfh 细胞基因转录。还在系统性红斑狼疮（SLE）患者的循环 Tfh 样细胞中确定 STAT4 依赖性信号传导和细胞因子产生，与健康对照受试者的细胞进行比较，并评估 SLE 患者 Tfh 样细胞中与疾病活动的相关性。
在狼疮倾向小鼠中检测到潜在致病性 IgG2c 自身抗体之前，IL-21 和 IFNγ 共产生的 Tfh 细胞就已经扩增。Tfh 细胞在疾病过程中进行转录进化，获得了依赖 STAT4 的基因特征。Tfh 细胞细胞因子合成的维持依赖于 STAT4 信号传导，由 I 型 IFNs 驱动。SLE 患者的循环 Tfh 样细胞也分泌 IL-21 和 IFNγ，IFNβ 增强 STAT4 磷酸化，与临床疾病活动程度相关。
我们在鼠和人类狼疮中确定了 I 型 IFN 信号传导在驱动 STAT4 激活和 Tfh 细胞产生 IL-21 和 IFNγ中的作用。Tfh 细胞中增强的 STAT4 激活可能是鼠和人类狼疮中致病性 B 细胞反应的基础。这些数据表明 STAT4 指导 SLE 中的致病性细胞因子和免疫球蛋白产生，表明这是一种潜在的治疗靶点，可调节自身免疫。
