Journal Article

The IL‐27/IL‐27R axis is altered in CD4+ and CD8+ T lymphocytes from multiple sclerosis patients

Duquette, Pierre, Devergne, Odile, Arbour, Nathalie, Farzam‐kia, Negar, Larochelle, Catherine, Lemaitre, Florent, Clénet, Marie‐Laure, Laurent, Cyril, Prat, Alexandre, Girard, Marc, Lahav, Boaz, Tastet, Olivier

2021

Overview

Objectives 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. Methods 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. Results 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. Conclusion 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. T lymphocytes play a central role in the pathobiology of chronic inflammatory diseases including multiple sclerosis (MS). We identified perturbations in the IL‐27/IL‐27R pathway in MS patients; IL‐27 triggers higher STAT3p response in T lymphocytes from MS vs. controls and induces PD‐L1 less efficiently on T cells from MS patients. Moreover, elevated IL‐27Rα levels in serum from MS patients, shed from activated CD4 T lymphocytes, are sufficient to impair the capacity of IL‐27 to act on immune cells.

• Publisher: John Wiley & Sons, Inc,Nature Publishing Group,John Wiley and Sons Inc,Wiley
• Subject: CD4 antigen / CD8 antigen / Cerebrospinal fluid / Cytokines / Disease / Flow cytometry / Gene expression / IL‐12 / Inflammatory diseases / Life Sciences / Lymphocytes / Lymphocytes T / Multiple sclerosis / neuroimmunology / Original / PD-L1 protein / PD‐L1 / Phosphorylation / Signal transduction / STAT signalling / Stat3 protein / T cells / Transcriptomes