The impact of fingolimod on Treg function in brain ischaemia

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Malone, Kyle
Shearer, Jennifer A.
Waeber, Christian
Moore, Anne C.
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John Wiley and Sons Inc
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Fingolimod 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.
FTY720 , Fingolimod , Ischaemia , Regulatory T cells , Stroke , Treg
Malone, K., Shearer, J.A., Waeber, C. and Moore, A.C. (2023) ‘The impact of fingolimod on Treg function in brain ischaemia’, European Journal of Immunology, 53(9), 2350370 (13pp) . doi: 10.1002/eji.202350370
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