Targeting abatacept-resistant T-helper-17 cells by aldehyde dehydrogenase inhibition
Summary: IL-17-producing helper T (Th17) cells are long-lived and serve as central effector cells in chronic autoimmune diseases. The underlying mechanisms of Th17 persistence remain unclear. We demonstrated that abatacept, a CD28 antagonist, effectively prevented the development of skin disease in...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223027232 |
| _version_ | 1797377809766678528 |
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| author | By Yukiko Tokifuji Hodaka Hayabuchi Takashi Sasaki Mariko Hara-Chikuma Keiji Hirota Hayato Takahashi Masayuki Amagai Akihiko Yoshimura Shunsuke Chikuma |
| author_facet | By Yukiko Tokifuji Hodaka Hayabuchi Takashi Sasaki Mariko Hara-Chikuma Keiji Hirota Hayato Takahashi Masayuki Amagai Akihiko Yoshimura Shunsuke Chikuma |
| author_sort | By Yukiko Tokifuji |
| collection | DOAJ |
| description | Summary: IL-17-producing helper T (Th17) cells are long-lived and serve as central effector cells in chronic autoimmune diseases. The underlying mechanisms of Th17 persistence remain unclear. We demonstrated that abatacept, a CD28 antagonist, effectively prevented the development of skin disease in a Th17-dependent experimental autoimmune dermatitis model. Abatacept selectively inhibited the emergence of IL-7R-negative effector-phenotype T cells while allowing the survival and proliferation of IL-7R+ memory-phenotype cells. The surviving IL-7R+ Th17 cells expressed genes associated with alcohol/aldehyde detoxification and showed potential to transdifferentiate into IL-7R-negative effector cells. Inhibiting aldehyde dehydrogenase reduced IL-7R+ Th17 cells in vivo, independently of CD28, and exhibited additive effects when combined with abatacept. Our findings suggest that CD28 blockade prevents inflammation without eliminating persistent memory cells. These remaining memory cells can be targeted by other drugs, such as aldehyde dehydrogenase inhibitors, to limit their survival, thereby facilitating the treatment of chronic autoimmune diseases. |
| first_indexed | 2024-03-08T19:57:46Z |
| format | Article |
| id | doaj.art-11c4d074d00245569a6675b9a7609b54 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-08T19:57:46Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-11c4d074d00245569a6675b9a7609b542023-12-24T04:46:16ZengElsevieriScience2589-00422024-01-01271108646Targeting abatacept-resistant T-helper-17 cells by aldehyde dehydrogenase inhibitionBy Yukiko Tokifuji0Hodaka Hayabuchi1Takashi Sasaki2Mariko Hara-Chikuma3Keiji Hirota4Hayato Takahashi5Masayuki Amagai6Akihiko Yoshimura7Shunsuke Chikuma8Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, East Lecture Hall 4F, Shinjuku, Tokyo 160-8582, JapanDepartment of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, East Lecture Hall 4F, Shinjuku, Tokyo 160-8582, JapanCenter for Supercentenarian Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, JapanDepartment of Pharmacology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, JapanLaboratory of Integrative Biological Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto 606-8507, JapanDepartment of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, JapanDepartment of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, JapanDepartment of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, East Lecture Hall 4F, Shinjuku, Tokyo 160-8582, JapanDepartment of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, East Lecture Hall 4F, Shinjuku, Tokyo 160-8582, Japan; Corresponding authorSummary: IL-17-producing helper T (Th17) cells are long-lived and serve as central effector cells in chronic autoimmune diseases. The underlying mechanisms of Th17 persistence remain unclear. We demonstrated that abatacept, a CD28 antagonist, effectively prevented the development of skin disease in a Th17-dependent experimental autoimmune dermatitis model. Abatacept selectively inhibited the emergence of IL-7R-negative effector-phenotype T cells while allowing the survival and proliferation of IL-7R+ memory-phenotype cells. The surviving IL-7R+ Th17 cells expressed genes associated with alcohol/aldehyde detoxification and showed potential to transdifferentiate into IL-7R-negative effector cells. Inhibiting aldehyde dehydrogenase reduced IL-7R+ Th17 cells in vivo, independently of CD28, and exhibited additive effects when combined with abatacept. Our findings suggest that CD28 blockade prevents inflammation without eliminating persistent memory cells. These remaining memory cells can be targeted by other drugs, such as aldehyde dehydrogenase inhibitors, to limit their survival, thereby facilitating the treatment of chronic autoimmune diseases.http://www.sciencedirect.com/science/article/pii/S2589004223027232Molecular biologyImmunityCell |
| spellingShingle | By Yukiko Tokifuji Hodaka Hayabuchi Takashi Sasaki Mariko Hara-Chikuma Keiji Hirota Hayato Takahashi Masayuki Amagai Akihiko Yoshimura Shunsuke Chikuma Targeting abatacept-resistant T-helper-17 cells by aldehyde dehydrogenase inhibition iScience Molecular biology Immunity Cell |
| title | Targeting abatacept-resistant T-helper-17 cells by aldehyde dehydrogenase inhibition |
| title_full | Targeting abatacept-resistant T-helper-17 cells by aldehyde dehydrogenase inhibition |
| title_fullStr | Targeting abatacept-resistant T-helper-17 cells by aldehyde dehydrogenase inhibition |
| title_full_unstemmed | Targeting abatacept-resistant T-helper-17 cells by aldehyde dehydrogenase inhibition |
| title_short | Targeting abatacept-resistant T-helper-17 cells by aldehyde dehydrogenase inhibition |
| title_sort | targeting abatacept resistant t helper 17 cells by aldehyde dehydrogenase inhibition |
| topic | Molecular biology Immunity Cell |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223027232 |
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