The impact of fingolimod on Treg function in brain ischaemia

Abstract

AbstractFingolimod has generally shown neuroprotective effects in stroke models. Here, we tested the hypothesis that fingolimod modulates T‐cell cytokine production towards a regulatory phenotype. Second, we investigated how fingolimod altered the Treg suppressive function and the sensitivity of effector T cells to regulation. Mice that had underwent the permanent electrocoagulation of the left middle cerebral artery received saline or fingolimod (0.5 mg/kg) daily for 10‐days post‐ischaemia. Fingolimod improved neurobehavioural recovery compared to saline control and increased Treg frequency in the periphery and brain. Tregs from fingolimod‐treated animals had a higher expression of CCR8. Fingolimod increased the frequencies of CD4+IL‐10+, CD4+ IFN‐γ+ and CD4+IL‐10+IFN‐γ+ cells in spleen and blood, and CD4+ IL‐17+ cells in the spleen, with only minor effects on CD8+ T‐cell cytokine production. Treg from post–ischaemic mice had reduced suppressive function compared to Treg from non‐ischaemic mice. Fingolimod treatment rescued this function against saline‐treated but not fingolimod‐treated CD4+ effector T cells. In conclusion, fingolimod seems to improve the suppressive function of Treg post‐stroke while also increasing the resistance of CD4+ effector cells to this suppression. Fingolimod's capacity to increase both effector and regulatory functions may explain the lack of consistent improvement in functional recovery in experimental brain ischaemia.