Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects

Luisa Klotz, Melanie Eschborn, Maren Lindner, Marie Liebmann, Martin Herold, Claudia Janoschka, Belén Torres Garrido, Andreas Schulte-Mecklenbeck, Catharina C. Gross, Johanna Breuer, Petra Hundehege, Vilmos Posevitz, Béatrice Pignolet, Giulia Nebel, Shirin Glander, Nicole Freise, Judith Austermann, Timo Wirth, Graham R. Campbell, Tilman Schneider-HohendorfMaria Eveslage, David Brassat, Nicholas Schwab, Karin Loser, Johannes Roth, Karin B. Busch, Monika Stoll, Don J. Mahad, Sven G. Meuth, Timothy Turner, Amit Bar-Or, Heinz Wiendl

Research output: Contribution to journalArticlepeer-review

Abstract

Interference with immune cell proliferation represents a successful treatment strategy in T cell–mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis (MS). One prominent example is pharmacological inhibition of dihydroorotate dehydrogenase (DHODH), which mediates de novo pyrimidine synthesis in actively proliferating T and B lymphocytes. Within the TERIDYNAMIC clinical study, we observed that the DHODH inhibitor teriflunomide caused selective changes in T cell subset composition and T cell receptor repertoire diversity in patients with relapsing-remitting MS (RRMS). In a preclinical antigen-specific setup, DHODH inhibition preferentially suppressed the proliferation of high-affinity T cells. Mechanistically, DHODH inhibition interferes with oxidative phosphorylation (OXPHOS) and aerobic glycolysis in activated T cells via functional inhibition of complex III of the respiratory chain. The affinity-dependent effects of DHODH inhibition were closely linked to differences in T cell metabolism. High-affinity T cells preferentially use OXPHOS during early activation, which explains their increased susceptibility toward DHODH inhibition. In a mouse model of MS, DHODH inhibitory treatment resulted in preferential inhibition of high-affinity autoreactive T cell clones. Compared to T cells from healthy controls, T cells from patients with RRMS exhibited increased OXPHOS and glycolysis, which were reduced with teriflunomide treatment. Together, these data point to a mechanism of action where DHODH inhibition corrects metabolic disturbances in T cells, which primarily affects profoundly metabolically active high-affinity T cell clones. Hence, DHODH inhibition may promote recovery of an altered T cell receptor repertoire in autoimmunity.
Original languageEnglish
Article numbereaao5563
Number of pages17
JournalScience Translational Medicine
Volume11
Issue number490
Early online date1 May 2019
DOIs
Publication statusE-pub ahead of print - 1 May 2019

Fingerprint Dive into the research topics of 'Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects'. Together they form a unique fingerprint.

Cite this