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Dimethyl fumerate (DMF) is an approved immune-modulatory drug for treatment of relapsing remitting multiple sclerosis (RRMS). Although DMF treatment leads to beneficial clinical effects, around 17% of patients develop a lymphopenia characterized by sustained decrease of lymphocyte counts within blood. In parallel, DMF-treated patients exhibited decreased frequencies of memory T cell (TM) while naïve T cells (TN) were less affected. Interestingly, it is known that TM cells reveal an increased metabolic capacity compared to TN cells, at least in the murine system.
The aim of this study was to investigate whether there is a DMF-mediated link between the T cell metabolism of different T cell subsets (TM and TN) and their T cell apoptosis. T cell metabolism and mitochondrial stress response was assessed using the Seahorse technology and fluorescent protein–based redox sensors, respectively. To determine apoptotic processes in T cells we performed flow-cytometric analysis of caspases 3 and 7.
T cells, which were isolated from peripheral blood mononuclear cells from MS patients before and during treatment with DMF, displayed a decreased T cell metabolism following DMF treatment. In vitro, DMF treatment of T cells isolated from healthy donors caused a diminished mitochondrial respiration of 75% in both T cell subsets (TM and TN cells), whereby TM cells displayed a 2-fold increased metabolic capacity compared to TN cells. In this line, we determined an enhanced mitochondrial stress response exhibited in evaluated ROS levels in DMF-treated TM cells, which strongly supports the idea that TM cells display an enhanced sensitivity upon DMF treatment. Correspondingly, DMF treatment revealed a higher apoptosis rate in TM cells than TN cells.
Collectively, these data illustrate that DMF treatment significantly reduces mitochondrial respiration in all T cell subsets. Importantly, TM cells display an enhanced sensitivity and stress response following DMF treatment, which might be a potential mechanisms explaining the increased apoptosis and vulnerability of TM cells in DMF-treated MS patients.
