Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects
Luisa Klotz
(1)
,
Melanie Eschborn
(1)
,
Maren Lindner
(1)
,
Marie Liebmann
(1)
,
Martin Herold
(1)
,
Claudia Janoschka
(1)
,
Belén Torres Garrido
(1)
,
Andreas Schulte-Mecklenbeck
(1)
,
Catharina Gross
(1)
,
Johanna Breuer
(1)
,
Petra Hundehege
(1)
,
Vilmos Posevitz
(1)
,
Béatrice Pignolet
(2, 3)
,
Giulia Nebel
(1)
,
Shirin Glander
(1)
,
Nicole Freise
(1)
,
Judith Austermann
(1)
,
Timo Wirth
(1)
,
Graham Campbell
(4)
,
Tilman Schneider-Hohendorf
(1)
,
Maria Eveslage
(1)
,
David Brassat
(2, 3)
,
Nicholas Schwab
(1)
,
Karin Loser
(1)
,
Johannes Roth
(1)
,
Karin Busch
(1)
,
Monika Stoll
(1, 5)
,
Don Mahad
(4)
,
Sven Meuth
(1)
,
Timothy Turner
(6)
,
Amit Bar-Or
(7)
,
Heinz Wiendl
(1, 8)
1
UKM -
University Hospital Münster - Universitaetsklinikum Muenster [Germany]
2 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
3 CPTP - Centre de Physiopathologie Toulouse Purpan
4 Edin. - University of Edinburgh
5 CARIM - Cardiovascular Research Institute Maastricht
6 Sanofi Genzyme
7 Perelman School of Medicine
8 The University of Sydney
2 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
3 CPTP - Centre de Physiopathologie Toulouse Purpan
4 Edin. - University of Edinburgh
5 CARIM - Cardiovascular Research Institute Maastricht
6 Sanofi Genzyme
7 Perelman School of Medicine
8 The University of Sydney
Luisa Klotz
- Fonction : Auteur
- PersonId : 763004
- ORCID : 0000-0001-5439-9633
Melanie Eschborn
- Fonction : Auteur
- PersonId : 823091
- ORCID : 0000-0003-4287-2678
Maren Lindner
- Fonction : Auteur
- PersonId : 823092
- ORCID : 0000-0002-7569-8912
Marie Liebmann
- Fonction : Auteur
- PersonId : 823093
- ORCID : 0000-0002-5565-5325
Martin Herold
- Fonction : Auteur
- PersonId : 780643
- ORCID : 0000-0002-3147-1281
Claudia Janoschka
- Fonction : Auteur
- PersonId : 823094
- ORCID : 0000-0003-0947-1805
Belén Torres Garrido
- Fonction : Auteur
- PersonId : 823095
- ORCID : 0000-0001-8765-3941
Andreas Schulte-Mecklenbeck
- Fonction : Auteur
- PersonId : 799597
- ORCID : 0000-0003-3855-4706
Catharina Gross
- Fonction : Auteur
- PersonId : 797472
- ORCID : 0000-0002-4872-9189
Petra Hundehege
- Fonction : Auteur
- PersonId : 823096
- ORCID : 0000-0001-9562-0285
Béatrice Pignolet
- Fonction : Auteur
- PersonId : 785161
- ORCID : 0000-0002-9351-2982
Nicole Freise
- Fonction : Auteur
- PersonId : 823097
- ORCID : 0000-0003-1842-973X
Graham Campbell
- Fonction : Auteur
- PersonId : 807168
- ORCID : 0000-0003-4828-421X
Tilman Schneider-Hohendorf
- Fonction : Auteur
- PersonId : 791880
- ORCID : 0000-0002-3717-5176
Maria Eveslage
- Fonction : Auteur
- PersonId : 823098
- ORCID : 0000-0002-8802-1134
David Brassat
- Fonction : Auteur
- PersonId : 773701
- ORCID : 0000-0001-6430-305X
Nicholas Schwab
- Fonction : Auteur
- PersonId : 791879
- ORCID : 0000-0001-5494-9885
Monika Stoll
- Fonction : Auteur
- PersonId : 796782
- ORCID : 0000-0002-2711-4281
Sven Meuth
- Fonction : Auteur
- PersonId : 794901
- ORCID : 0000-0003-2571-3501
Résumé
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.