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

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.