Inhibition of mitochondrial respiration with teriflunomide modulates antigen-specific immune responses in an affinity-dependent fashion
M. Lindner1+, M. Eschborn1+, L. Klotz1+, M. Liebmann1, B. T. Garrido1, J. Breuer1, N. Schwab1, C.C. Gross1, A. Schulte-Mecklenbeck1, P. Hundehege1, G. Nebel2, S. Glander3, K. Busch2, M. Stoll3, M. Eveslage4, S. Meuth1, T. Turner5, A. Bar-Or6, H. Wiendl1 on behalf of the TERIDYNAMIC study group
1University Hospital Münster, Department of Neurology, Münster, DE; 2University of Münster, Institute for Molecular Cell Biology, Münster, DE; 3University of Münster, Core Facility Genomics, Münster, DE; 4University of Münster, Institute for Biometrics and Clinical Research, Münster, DE; 5Sanofi Genzyme, Cambridge, MA, USA; 6Montreal Neurological Institute, Montreal, QC, Canada
Teriflunomide (TF) is an immunmodulatory drug used for treatment of T cell mediated autoimmune diseases e.g. rheumatoid arthritis and multiple sclerosis. Its capacity to inhibit the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) of the de novo pyrimidine synthesis pathway translates into a reduced proliferation of activated immune cells. Pharmacological DHODH inhibition via TF reduces levels of mitochondrial respiration and glycolysis in T cells. Here, we provide first evidence that TF suppresses T cell proliferation and metabolism in an affinity dependent manner meaning that high affinity T cells are more impaired by DHODH inhibition than low affinity T cells. Kinetics of high affinity T cells revealed that they increase mitochondrial respiration more rapidly than low affinity T cells in the early phase of activation which explains their enlarged susceptibility towards DHODH inhibition. In the MOG-EAE model we could proof that treatment with leflunomide (precursor of TF) results in a preferential reduction of high-affinity T cells by using 2-D microscopy. Hence, we hypothesize that DHODH inhibition in vivo results in an altered T cell clonal repertoire, a concept which is supported by data from a clinical trial employing the DHODH inhibitor teriflunomide in RRMS patients (TERIDYNAMIC trial). Taken together, our data suggest that the affinity of the peptide-TCR-interaction directs the mode of energy production in T cells and can therefore be specifically targeted via DHODH inhibition.