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-27R alpha in MS patients. Methods. Levels of IL-27 and its natural antagonist (IL-27-R alpha) 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-27R alpha, 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-27R alpha 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-27R alpha by activated CD4(+) T lymphocytes from MS patients contributes to the increased IL-27R alpha 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.