Teriflunomide Treatment of Multiple Sclerosis Selectively Modulates CD8 Memory T Cells
Background and ObjectivesInhibition of de novo pyrimidine synthesis in proliferating T and B lymphocytes by teriflunomide, a pharmacological inhibitor of dihydroorotate dehydrogenase (DHODH), has been shown to be an effective therapy to treat patients with MS in placebo-controlled phase 3 trials. Ne...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.730342/full |
| _version_ | 1818620415093768192 |
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| author | Gaëlle Tilly Marion Cadoux Alexandra Garcia Jérémy Morille Sandrine Wiertlewski Sandrine Wiertlewski Claire Pecqueur Sophie Brouard David Laplaud David Laplaud Nicolas Degauque |
| author_facet | Gaëlle Tilly Marion Cadoux Alexandra Garcia Jérémy Morille Sandrine Wiertlewski Sandrine Wiertlewski Claire Pecqueur Sophie Brouard David Laplaud David Laplaud Nicolas Degauque |
| author_sort | Gaëlle Tilly |
| collection | DOAJ |
| description | Background and ObjectivesInhibition of de novo pyrimidine synthesis in proliferating T and B lymphocytes by teriflunomide, a pharmacological inhibitor of dihydroorotate dehydrogenase (DHODH), has been shown to be an effective therapy to treat patients with MS in placebo-controlled phase 3 trials. Nevertheless, the underlying mechanism contributing to the efficacy of DHODH inhibition has been only partially elucidated. Here, we aimed to determine the impact of teriflunomide on the immune compartment in a longitudinal high-dimensional follow-up of patients with relapse-remitting MS (RRMS) treated with teriflunomide.MethodsHigh-dimensional spectral flow cytometry was used to analyze the phenotype and the function of innate and adaptive immune system of patients with RRMS before and 12 months after teriflunomide treatment. In addition, we assessed the impact of teriflunomide on the migration of memory CD8 T cells in patients with RRMS, and we defined patient immune metabolic profiles.ResultsWe found that 12 months of treatment with teriflunomide in patients with RRMS does not affect the B cell or CD4 T cell compartments, including regulatory TREG follicular helper TFH cell and helper TH cell subsets. In contrast, we observed a specific impact of teriflunomide on the CD8 T cell compartment, which was characterized by decreased homeostatic proliferation and reduced production of TNFα and IFNγ. Furthermore, we showed that DHODH inhibition also had a negative impact on the migratory velocity of memory CD8 T cells in patients with RRMS. Finally, we showed that the susceptibility of memory CD8 T cells to DHODH inhibition was not related to impaired metabolism.DiscussionOverall, these findings demonstrate that the clinical efficacy of teriflunomide results partially in the specific susceptibility of memory CD8 T cells to DHODH inhibition in patients with RRMS and strengthens active roles for these T cells in the pathophysiological process of MS. |
| first_indexed | 2024-12-16T17:53:01Z |
| format | Article |
| id | doaj.art-a07d9ea562304e78906881830d7bc40a |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-16T17:53:01Z |
| publishDate | 2021-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-a07d9ea562304e78906881830d7bc40a2022-12-21T22:22:15ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-10-011210.3389/fimmu.2021.730342730342Teriflunomide Treatment of Multiple Sclerosis Selectively Modulates CD8 Memory T CellsGaëlle Tilly0Marion Cadoux1Alexandra Garcia2Jérémy Morille3Sandrine Wiertlewski4Sandrine Wiertlewski5Claire Pecqueur6Sophie Brouard7David Laplaud8David Laplaud9Nicolas Degauque10Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, FranceUniversité de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, FranceUniversité de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, FranceUniversité de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, FranceUniversité de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, FranceCHU Nantes, Service de Neurologie, CRC-SEP, CIC1413, Nantes, FranceUniversité de Nantes, CRCINA, INSERM, CNRS, Nantes, FranceUniversité de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, FranceUniversité de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, FranceCHU Nantes, Service de Neurologie, CRC-SEP, CIC1413, Nantes, FranceUniversité de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, FranceBackground and ObjectivesInhibition of de novo pyrimidine synthesis in proliferating T and B lymphocytes by teriflunomide, a pharmacological inhibitor of dihydroorotate dehydrogenase (DHODH), has been shown to be an effective therapy to treat patients with MS in placebo-controlled phase 3 trials. Nevertheless, the underlying mechanism contributing to the efficacy of DHODH inhibition has been only partially elucidated. Here, we aimed to determine the impact of teriflunomide on the immune compartment in a longitudinal high-dimensional follow-up of patients with relapse-remitting MS (RRMS) treated with teriflunomide.MethodsHigh-dimensional spectral flow cytometry was used to analyze the phenotype and the function of innate and adaptive immune system of patients with RRMS before and 12 months after teriflunomide treatment. In addition, we assessed the impact of teriflunomide on the migration of memory CD8 T cells in patients with RRMS, and we defined patient immune metabolic profiles.ResultsWe found that 12 months of treatment with teriflunomide in patients with RRMS does not affect the B cell or CD4 T cell compartments, including regulatory TREG follicular helper TFH cell and helper TH cell subsets. In contrast, we observed a specific impact of teriflunomide on the CD8 T cell compartment, which was characterized by decreased homeostatic proliferation and reduced production of TNFα and IFNγ. Furthermore, we showed that DHODH inhibition also had a negative impact on the migratory velocity of memory CD8 T cells in patients with RRMS. Finally, we showed that the susceptibility of memory CD8 T cells to DHODH inhibition was not related to impaired metabolism.DiscussionOverall, these findings demonstrate that the clinical efficacy of teriflunomide results partially in the specific susceptibility of memory CD8 T cells to DHODH inhibition in patients with RRMS and strengthens active roles for these T cells in the pathophysiological process of MS.https://www.frontiersin.org/articles/10.3389/fimmu.2021.730342/fullmultiple sclerosisteriflunomideCD8 T cellsCD4 T cellsmigrationmemory T cells |
| spellingShingle | Gaëlle Tilly Marion Cadoux Alexandra Garcia Jérémy Morille Sandrine Wiertlewski Sandrine Wiertlewski Claire Pecqueur Sophie Brouard David Laplaud David Laplaud Nicolas Degauque Teriflunomide Treatment of Multiple Sclerosis Selectively Modulates CD8 Memory T Cells Frontiers in Immunology multiple sclerosis teriflunomide CD8 T cells CD4 T cells migration memory T cells |
| title | Teriflunomide Treatment of Multiple Sclerosis Selectively Modulates CD8 Memory T Cells |
| title_full | Teriflunomide Treatment of Multiple Sclerosis Selectively Modulates CD8 Memory T Cells |
| title_fullStr | Teriflunomide Treatment of Multiple Sclerosis Selectively Modulates CD8 Memory T Cells |
| title_full_unstemmed | Teriflunomide Treatment of Multiple Sclerosis Selectively Modulates CD8 Memory T Cells |
| title_short | Teriflunomide Treatment of Multiple Sclerosis Selectively Modulates CD8 Memory T Cells |
| title_sort | teriflunomide treatment of multiple sclerosis selectively modulates cd8 memory t cells |
| topic | multiple sclerosis teriflunomide CD8 T cells CD4 T cells migration memory T cells |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.730342/full |
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