Induction of gut regulatory CD39(+) T cells by teriflunomide protects against EAE

OBJECTIVE: To determine whether as an orally delivered treatment, teriflunomide, an inhibitor of the mitochondrial enzyme dihydroorotate dehydrogenase approved to treat relapsing forms of multiple sclerosis, could affect gut-associated lymphoid tissue (GALT) immune responses functionally. METHODS: C57BL/6 mice were treated orally with teriflunomide and flow cytometric analysis of immune GALT cells performed ex vivo, and adoptive transfer experiments were used to test the protective effects of GALT regulatory T (Treg) cells. RESULTS: Teriflunomide reduced the percentages of antigen-presenting cells of Peyer patches when compared to controls. Conversely, a significant increase of the relative frequency of CD39(+) Treg cells was observed. In vivo, the protective effect of GALT-derived teriflunomide-induced CD39(+) Treg cells was established by adoptive transfer into recipient experimental autoimmune encephalomyelitis mice. CONCLUSIONS: Our results identify specific GALT-derived CD39(+) Treg cells as a mechanism of action that may contribute to the efficacy of teriflunomide during CNS inflammatory demyelination and as an oral therapeutic in relapsing multiple sclerosis.