TY - JOUR
T1 - Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects
AU - Klotz, Luisa
AU - Eschborn, Melanie
AU - Lindner, Maren
AU - Liebmann, Marie
AU - Herold, Martin
AU - Janoschka, Claudia
AU - Garrido, Belen Torres
AU - Schulte-Mecklenbeck, Andreas
AU - Gross, Catharina C.
AU - Breuer, Johanna
AU - Hundehege, Petra
AU - Posevitz, Vilmos
AU - Pignolet, Beatrice
AU - Nebel, Giulia
AU - Glander, Shirin
AU - Freise, Nicole
AU - Austermann, Judith
AU - Wirth, Timo
AU - Campbell, Graham R.
AU - Schneider-Hohendorf, Tilman
AU - Eveslage, Maria
AU - Brassat, David
AU - Schwab, Nicholas
AU - Loser, Karin
AU - Roth, Johannes
AU - Busch, Karin B.
AU - Stoll, Monika
AU - Mahad, Don J.
AU - Meuth, Sven G.
AU - Turner, Timothy
AU - Bar-Or, Amit
AU - Wiendl, Heinz
PY - 2019/5/1
Y1 - 2019/5/1
N2 - 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.
AB - 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.
KW - RHEUMATOID-ARTHRITIS
KW - NEGATIVE SELECTION
KW - AVIDITY MATURATION
KW - LEFLUNOMIDE
KW - TCR
U2 - 10.1126/scitranslmed.aao5563
DO - 10.1126/scitranslmed.aao5563
M3 - Article
C2 - 31043571
VL - 11
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 490
M1 - 5563
ER -