Research ArticleMultiple Sclerosis

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

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Science Translational Medicine  01 May 2019:
Vol. 11, Issue 490, eaao5563
DOI: 10.1126/scitranslmed.aao5563

Teriflunomide tampers with T cells

Activated T cells need de novo pyrimidine biosynthesis, which has been exploited for autoimmune therapy. Klotz et al. studied samples from patients with multiple sclerosis treated with the dihydroorotate dehydrogenase inhibitor teriflunomide. They found that teriflunomide did not affect all T cells equally and led to repertoire and subset distribution changes. They also used a mouse model of T cells with higher and lower affinity for the same antigen to explore the drug’s effects. Collectively, their data demonstrate that high-affinity T cells preferentially use mitochondrial respiration, which is then inhibited by teriflunomide.


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.

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