Clénet Marie-Laure, Laurent Cyril, Lemaitre Florent, Farzam-Kia Negar, Tastet Olivier, Devergne Odile, Lahav Boaz, Girard Marc, Duquette Pierre, Prat Alexandre, Larochelle Catherine, Arbour Nathalie
Department of Neurosciences Université de Montréal and CRCHUM Montreal QC Canada.
INSERM CNRS Centre d'Immunologie et des Maladies Infectieuses Sorbonne Université Paris France.
Clin Transl Immunology. 2021 Mar 5;10(3):e1262. doi: 10.1002/cti2.1262. eCollection 2021.
Pro- and anti-inflammatory properties have been attributed to interleukin-27 (IL-27). Nevertheless, the impact of this cytokine on chronic inflammatory diseases such as multiple sclerosis (MS) remains ill-defined. We investigated the biology of IL-27 and its specific receptor IL-27Rα in MS patients.
Levels of IL-27 and its natural antagonist (IL-27-Rα) were measured by ELISA in biological fluids. CD4 and CD8 T lymphocytes were isolated from untreated relapsing-remitting MS patients and healthy donors. Transcriptome-wide analysis compared T-cell subsets stimulated or not with IL-27. Expression of the IL-27Rα, key immune factors, STAT phosphorylation and cytokine production was assessed by flow cytometry.
We observed elevated levels of IL-27 in the serum and cerebrospinal fluid of MS patients compared with controls. Moreover, we show that specific IL-27-mediated effects on T lymphocytes are reduced in MS patients including the induction of PD-L1. IL-27-triggered STAT3 signalling pathway is enhanced in CD4 and CD8 T lymphocytes from MS patients. Elevated IL-27Rα levels in serum from MS patients are sufficient to impair the capacity of IL-27 to act on immune cells. We demonstrate that shedding of IL-27Rα by activated CD4 T lymphocytes from MS patients contributes to the increased IL-27Rα peripheral levels and consequently can dampen the IL-27 responsiveness.
Our work identifies several mechanisms that are altered in the IL-27/IL-27R axis in MS patients, especially in T lymphocytes. Our results underline the importance of characterising the biology of cytokines in human patients prior to design new therapeutics.
白细胞介素-27（IL-27）具有促炎和抗炎特性。然而，这种细胞因子对诸如多发性硬化症（MS）等慢性炎症性疾病的影响仍不明确。我们研究了MS患者中IL-27及其特异性受体IL-27Rα的生物学特性。
通过酶联免疫吸附测定法（ELISA）测量生物体液中IL-27及其天然拮抗剂（IL-27-Rα）的水平。从未经治疗的复发缓解型MS患者和健康供体中分离出CD4和CD8 T淋巴细胞。全转录组分析比较了用IL-27刺激或未刺激的T细胞亚群。通过流式细胞术评估IL-27Rα的表达、关键免疫因子、信号转导和转录激活因子（STAT）磷酸化以及细胞因子产生情况。
与对照组相比，我们观察到MS患者血清和脑脊液中IL-27水平升高。此外，我们发现MS患者中IL-27对T淋巴细胞的特异性作用降低，包括程序性死亡配体1（PD-L1）的诱导。在MS患者的CD4和CD8 T淋巴细胞中，IL-27触发的信号转导和转录激活因子3（STAT3）信号通路增强。MS患者血清中升高的IL-27Rα水平足以削弱IL-27作用于免疫细胞的能力。我们证明，MS患者活化的CD4 T淋巴细胞使IL-27Rα脱落，导致外周血中IL-27Rα水平升高，从而减弱IL-27反应性。
我们的研究确定了MS患者IL-27/IL-27R轴中几种发生改变的机制，尤其是在T淋巴细胞中。我们的结果强调了在设计新疗法之前了解人类患者细胞因子生物学特性的重要性。
