IL-6 and IL-27 negatively regulate CRTAM-expressing CD4+ T-cells associated with lymphoid-driven synovitis.

Alicia Derrac Soria, Myles J Lewis, Xiao Liu, Jason P Twohig, Federica Monaco, Sandra Dimonte, Ana Cardus Figueras, Aisling Morrin, Carol Guy, Benjamin C Cossins, Robert Benson, Robert Andrews, Ernest H Choy, Paul Garside, Muneerah Huwaikem, Marc P Stemmler, Simone Brabletz, Thomas Brabletz, Florian A Siebzehnrubl, Neil Rodrigues, Brendan J Jenkins, Costantino Pitzalis, Gareth W Jones, Simon A Jones
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Abstract

Joint pathology in rheumatoid arthritis is heterogeneous, with histology providing evidence of fibroblast-driven, myeloid-driven, and lymphoid-driven synovitis. However, the immuno-modulatory pathways underlying their development remain unclear. Profiling synovial tissues from rheumatoid arthritis patients and mice with antigen-induced arthritis, we identified a subset of synovial infiltrating CD4+ T-cells expressing CRTAM (class-I MHC-restricted T-cell-associated molecule). In human synovial biopsies, CRTAM correlated with the expression of effector cytokines (IL21, IFNG), chemokine receptors (CXCR3, CXCR4, CCR5), granzymes (GZMA, GZMB, GZMK), and regulatory factors (TIGIT, EOMES, BATF) linked with T-cell-mediated immunity. Studies of antigen-induced arthritis showed that CRTAM+CD4+ T-cells accumulate in the inflamed synovium following disease onset. CRTAM+CD4+ T-cells were particularly abundant in synovial tissue from Il27ra-/- mice displaying ectopic lymphoid-like structures. CADM1 (cell adhesion molecule-1), the endogenous ligand for CRTAM, was also expressed in human synovitis and synovial tissues from wild-type, Il6ra-/-, and Il27ra-/- mice with antigen-induced arthritis. Cells expressing human CADM1 included synovial fibroblasts and subsets of monocytic and CD19+ cells. Considering the ex vivo regulation of CRTAM, we identified that activation of naive CD4+ T-cell increased CRTAM expression. This induction was blocked by IL-6 and IL-27, with further studies identifying a role for STAT3 in controlling the CRTAM transcriptional repressor, ZEB1. These results provide insights into the cytokine control of CRTAM on CD4+ T-cells and support the involvement of CRTAM+CD4+ T-cells in lymphoid-driven synovitis.
IL-6和IL-27对与淋巴细胞驱动的滑膜炎相关的CRTAM表达CD4+T细胞有负向调节作用。
类风湿性关节炎的关节病理变化多种多样,组织学显示有成纤维细胞驱动型、髓细胞驱动型和淋巴细胞驱动型滑膜炎。然而,这些滑膜炎发生的免疫调节途径仍不清楚。通过分析类风湿性关节炎患者和抗原诱导关节炎小鼠的滑膜组织,我们发现了一个表达 CRTAM(I 类 MHC 限制性 T 细胞相关分子)的 CD4+ T 细胞浸润滑膜亚群。在人体滑膜活检中,CRTAM 与效应细胞因子(IL21、IFNG)、趋化因子受体(CXCR3、CXCR4、CCR5)、颗粒酶(GZMA、GZMB、GZMK)以及与 T 细胞介导的免疫相关的调节因子(TIGIT、EOMES、BATF)的表达相关。对抗原诱导的关节炎的研究表明,CRTAM+CD4+ T 细胞会在发病后积聚在发炎的滑膜中。在显示异位淋巴样结构的 Il27ra-/- 小鼠滑膜组织中,CRTAM+CD4+ T 细胞尤其丰富。CADM1(细胞粘附分子-1)是CRTAM的内源性配体,在人类滑膜炎以及野生型、Il6ra-/-和Il27ra-/-小鼠抗原诱发关节炎的滑膜组织中也有表达。表达人 CADM1 的细胞包括滑膜成纤维细胞以及单核细胞和 CD19+ 细胞亚群。考虑到 CRTAM 的体内外调控,我们发现激活幼稚 CD4+ T 细胞会增加 CRTAM 的表达。这种诱导作用被 IL-6 和 IL-27 阻断,进一步研究发现 STAT3 在控制 CRTAM 转录抑制因子 ZEB1 中的作用。这些结果为细胞因子控制 CD4+ T 细胞上的 CRTAM 提供了见解,并支持 CRTAM+CD4+ T 细胞参与淋巴驱动的滑膜炎。
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