Department of Neurosciences, Université de Montréal and Centre de Recherche du CHUM (CRCHUM), 900 St-Denis Street, Room R09.464, Montreal, QC, H2X 0A9, Canada.
Centre de Recherche du Centre Hospitalier de L'Université de Montréal (CRCHUM), Montreal, QC, Canada.
J Neuroinflammation. 2022 Sep 1;19(1):212. doi: 10.1186/s12974-022-02572-1.
Interleukin-27 (IL-27) can trigger both pro- and anti-inflammatory responses. This cytokine is elevated in the central nervous system (CNS) of multiple sclerosis (MS) patients, but how it influences neuroinflammatory processes remains unclear. As astrocytes express the receptor for IL-27, we sought to determine how these glial cells respond to this cytokine and whether such exposure alters their interactions with infiltrating activated T lymphocytes. To determine whether inflammation shapes the impact of IL-27, we compared the effects of this cytokine in non-inflamed and inflamed conditions induced by an IL-1β exposure.
Transcriptomic analysis of IL-27-exposed human astrocytes showed an upregulation of multiple immune genes. Human astrocytes increased the secretion of chemokines (CXCL9, CXCL10, and CXCL11) and the surface expression of proteins (PD-L1, HLA-E, and ICAM-1) following IL-27 exposure. To assess whether exposure of astrocytes to IL-27 influences the profile of activated T lymphocytes infiltrating the CNS, we used an astrocyte/T lymphocyte co-culture model. Activated human CD4 or CD8 T lymphocytes were co-cultured with astrocytes that have been either untreated or pre-exposed to IL‑27 or IL-1β. After 24 h, we analyzed T lymphocytes by flow cytometry for transcription factors and immune molecules. The contact with IL-27-exposed astrocytes increased the percentages of T-bet, Eomes, CD95, IL-18Rα, ICAM-1, and PD-L1 expressing CD4 and CD8 T lymphocytes and reduced the proportion of CXCR3-positive CD8 T lymphocytes. Human CD8 T lymphocytes co-cultured with human IL-27-treated astrocytes exhibited higher motility than when in contact with untreated astrocytes. These results suggested a preponderance of kinapse-like over synapse-like interactions between CD8 T lymphocytes and IL-27-treated astrocytes. Finally, CD8 T lymphocytes from MS patients showed higher motility in contact with IL-27-exposed astrocytes compared to healthy donors' cells.
Our results establish that IL-27 alters the immune functions of human astrocytes and shapes the profile and motility of encountered T lymphocytes, especially CD8 T lymphocytes from MS patients.
白细胞介素 27（IL-27）既能引发促炎反应，也能引发抗炎反应。多发性硬化症（MS）患者的中枢神经系统（CNS）中白细胞介素 27 水平升高，但它如何影响神经炎症过程尚不清楚。由于星形胶质细胞表达白细胞介素 27 的受体，我们试图确定这些神经胶质细胞对这种细胞因子的反应，以及这种暴露是否改变它们与浸润的活化 T 淋巴细胞的相互作用。为了确定炎症是否会影响白细胞介素 27 的作用，我们比较了在白细胞介素 1β 暴露引起的非炎症和炎症条件下，这种细胞因子的作用。
白细胞介素 27 暴露的人星形胶质细胞的转录组分析显示，多种免疫基因上调。白细胞介素 27 暴露后，人星形胶质细胞增加趋化因子（CXCL9、CXCL10 和 CXCL11）的分泌和表面蛋白（PD-L1、HLA-E 和 ICAM-1）的表达。为了评估星形胶质细胞暴露于白细胞介素 27 是否会影响浸润中枢神经系统的活化 T 淋巴细胞的表型，我们使用了星形胶质细胞/T 淋巴细胞共培养模型。未经处理或预先用白细胞介素-27 或白细胞介素-1β 处理的星形胶质细胞与活化的人 CD4 或 CD8 T 淋巴细胞共培养。24 小时后，我们通过流式细胞术分析 T 淋巴细胞中的转录因子和免疫分子。与白细胞介素 27 暴露的星形胶质细胞接触会增加表达 T-bet、Eomes、CD95、IL-18Rα、ICAM-1 和 PD-L1 的 CD4 和 CD8 T 淋巴细胞的百分比，并减少 CXCR3 阳性 CD8 T 淋巴细胞的比例。与未经处理的星形胶质细胞接触相比，与人类白细胞介素-27 处理的星形胶质细胞共培养的人类 CD8 T 淋巴细胞表现出更高的迁移率。这些结果表明，CD8 T 淋巴细胞与白细胞介素 27 处理的星形胶质细胞之间存在更多的类突触而非突触样相互作用。最后，与健康供体细胞相比，来自多发性硬化症患者的 CD8 T 淋巴细胞与暴露于白细胞介素 27 的星形胶质细胞接触时表现出更高的迁移率。
我们的研究结果表明，白细胞介素 27 改变了人星形胶质细胞的免疫功能，并塑造了遇到的 T 淋巴细胞，尤其是多发性硬化症患者的 CD8 T 淋巴细胞的表型和迁移率。
