Department of Rheumatology, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
Arthritis Res Ther. 2021 Jun 3;23(1):157. doi: 10.1186/s13075-021-02532-9.
Chronic synovial inflammation is an important hallmark of inflammatory arthritis, but the cells and mechanisms involved are incompletely understood. Previously, we have shown that CCR6+ memory T-helper (memTh) cells and synovial fibroblasts (SF) activate each other in a pro-inflammatory feedforward loop, which potentially drives persistent synovial inflammation in inflammatory arthritis. However, the CCR6+ memTh cells are a heterogeneous population, containing Th17/Th22 and Th17.1 cells. Currently, it is unclear which of these subpopulations drive SF activation and how they should be targeted. In this study, we examined the individual contribution of these CCR6+ memTh subpopulations to SF activation and examined ways to regulate their function.
Th17/Th22 (CXCR3CCR4), Th17.1 (CXCR3CCR4), DP (CXCR3CCR4), and DN (CXCR3CCR4) CCR6+ memTh, cells sorted from PBMC of healthy donors or treatment-naïve early rheumatoid arthritis (RA) patients, were cocultured with SF from RA patients with or without anti-IL17A, anti-IFNγ, or 1,25(OH)D. Cultures were analyzed by RT-PCR, ELISA, or flow cytometry.
Th17/Th22, Th17.1, DP, and DN cells equally express RORC but differ in production of TBX21 and cytokines like IL-17A and IFNγ. Despite these differences, all the individual CCR6+ memTh subpopulations, both from healthy individuals and RA patients, were more potent in activating SF than the classical Th1 cells. SF activation was partially inhibited by blocking IL-17A, but not by inhibiting IFNγ or TBX21. However, active vitamin D inhibited the pathogenicity of all subpopulations leading to suppression of SF activation.
Human CCR6+ memTh cells contain several subpopulations that equally express RORC but differ in TBX21, IFNγ, and IL-17A expression. All individual Th17 subpopulations are more potent in activating SF than classical Th1 cells in an IFNγ-independent manner. Furthermore, our data suggest that IL-17A is not dominant in this T cell-SF activation loop but that a multiple T cell cytokine inhibitor, such as 1,25(OH)D, is able to suppress CCR6+ memTh subpopulation-driven SF activation.
慢性滑膜炎症是炎症性关节炎的一个重要标志，但涉及的细胞和机制尚不完全清楚。此前，我们已经表明，CCR6+记忆性辅助性 T 细胞（memTh）和滑膜成纤维细胞（SF）在一个促炎的前馈回路中相互激活，这可能导致炎症性关节炎中持续性滑膜炎症。然而，CCR6+memTh 细胞是一个异质群体，包含 Th17/Th22 和 Th17.1 细胞。目前，尚不清楚这些亚群中的哪一种会驱动 SF 的激活，以及应该如何针对它们进行治疗。在这项研究中，我们研究了这些 CCR6+memTh 亚群对 SF 激活的单独贡献，并研究了调节其功能的方法。
从健康供体或未经治疗的早期类风湿关节炎（RA）患者的 PBMC 中分离出 Th17/Th22（CXCR3CCR4）、Th17.1（CXCR3CCR4）、DP（CXCR3CCR4）和 DN（CXCR3CCR4）CCR6+memTh 细胞，与来自 RA 患者的 SF 共培养，有或没有抗 IL17A、抗 IFNγ 或 1,25（OH）D。通过 RT-PCR、ELISA 或流式细胞术分析培养物。
Th17/Th22、Th17.1、DP 和 DN 细胞均表达 RORC，但 TBX21 和细胞因子如 IL-17A 和 IFNγ 的产生不同。尽管存在这些差异，但来自健康个体和 RA 患者的所有单个 CCR6+memTh 亚群都比经典 Th1 细胞更能激活 SF。SF 的激活部分被阻断 IL-17A 抑制，但不能被阻断 IFNγ 或 TBX21 抑制。然而，活性维生素 D 抑制了所有亚群的致病性，导致 SF 激活受到抑制。
人类 CCR6+memTh 细胞包含几个亚群，它们均表达 RORC，但在 TBX21、IFNγ 和 IL-17A 的表达上存在差异。所有单个 Th17 亚群在 IFNγ 非依赖性方式下比经典 Th1 细胞更能有效地激活 SF。此外，我们的数据表明，在这个 T 细胞-SF 激活环中，IL-17A 并不是主导因素，而是一种多种 T 细胞细胞因子抑制剂，如 1,25（OH）D，能够抑制 CCR6+memTh 亚群驱动的 SF 激活。
Zotero 插件
