TIGIT deficiency promotes autoreactive CD4+ T-cell responses through a metabolic‒epigenetic mechanism in autoimmune myositis
Abstract Polymyositis (PM) is a systemic autoimmune disease characterized by muscular inflammatory infiltrates and degeneration. T-cell immunoreceptor with Ig and ITIM domains (TIGIT) contributes to immune tolerance by inhibiting T cell-mediated autoimmunity. Here, we show that a reduced expression...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59786-z |
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| author | Yimei Lai Shuang Wang Tingting Ren Jia Shi Yichao Qian Shuyi Wang Mianjing Zhou Ryu Watanabe Mengyuan Li Xinyuan Ruan Xin Wang Lili Zhuang Zunfu Ke Niansheng Yang Yuefang Huang Hui Zhang |
| author_facet | Yimei Lai Shuang Wang Tingting Ren Jia Shi Yichao Qian Shuyi Wang Mianjing Zhou Ryu Watanabe Mengyuan Li Xinyuan Ruan Xin Wang Lili Zhuang Zunfu Ke Niansheng Yang Yuefang Huang Hui Zhang |
| author_sort | Yimei Lai |
| collection | DOAJ |
| description | Abstract Polymyositis (PM) is a systemic autoimmune disease characterized by muscular inflammatory infiltrates and degeneration. T-cell immunoreceptor with Ig and ITIM domains (TIGIT) contributes to immune tolerance by inhibiting T cell-mediated autoimmunity. Here, we show that a reduced expression of TIGIT in CD4+ T cells from patients with PM promotes these cells’ differentiation into Th1 and Th17 cells, which could be rescued by TIGIT overexpression. Knockout of TIGIT enhances muscle inflammation in a mouse model of experimental autoimmune myositis. Mechanistically, we find that TIGIT deficiency enhances CD28-mediated PI3K/AKT/mTOR co-stimulatory pathway, which promotes glucose oxidation, citrate production, and increased cytosolic acetyl-CoA levels, ultimately inducing epigenetic reprogramming via histone acetylation. Importantly, pharmacological inhibition of histone acetylation suppresses the differentiation of Th1 and Th17 cells, alleviating muscle inflammation. Thus, our findings reveal a mechanism by which TIGIT directly affects the differentiation of Th1 and Th17 T cells through metabolic‒epigenetic reprogramming, with important implications for treating systemic autoimmune diseases. |
| format | Article |
| id | doaj-art-ca355d6ba28a4a7180723414d8d830ff |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ca355d6ba28a4a7180723414d8d830ff2025-08-20T03:53:58ZengNature PortfolioNature Communications2041-17232025-05-0116112410.1038/s41467-025-59786-zTIGIT deficiency promotes autoreactive CD4+ T-cell responses through a metabolic‒epigenetic mechanism in autoimmune myositisYimei Lai0Shuang Wang1Tingting Ren2Jia Shi3Yichao Qian4Shuyi Wang5Mianjing Zhou6Ryu Watanabe7Mengyuan Li8Xinyuan Ruan9Xin Wang10Lili Zhuang11Zunfu Ke12Niansheng Yang13Yuefang Huang14Hui Zhang15Department of Rheumatology and Clinical immunology, the First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Rheumatology and Clinical immunology, the First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Rheumatology and Clinical immunology, the First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Rheumatology and Clinical immunology, the First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Rheumatology and Clinical immunology, the First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Rheumatology and Clinical immunology, the First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Rheumatology and Clinical immunology, the First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Clinical Immunology, Osaka Metropolitan University Graduate School of MedicineDepartment of Rheumatology and Clinical immunology, the First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Rheumatology and Clinical immunology, the First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Pediatrics, the First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Rheumatology and Clinical immunology, the First Affiliated Hospital of Sun Yat-sen UniversityInstitute of Precision Medicine, the First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Rheumatology and Clinical immunology, the First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Pediatrics, the First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Rheumatology and Clinical immunology, the First Affiliated Hospital of Sun Yat-sen UniversityAbstract Polymyositis (PM) is a systemic autoimmune disease characterized by muscular inflammatory infiltrates and degeneration. T-cell immunoreceptor with Ig and ITIM domains (TIGIT) contributes to immune tolerance by inhibiting T cell-mediated autoimmunity. Here, we show that a reduced expression of TIGIT in CD4+ T cells from patients with PM promotes these cells’ differentiation into Th1 and Th17 cells, which could be rescued by TIGIT overexpression. Knockout of TIGIT enhances muscle inflammation in a mouse model of experimental autoimmune myositis. Mechanistically, we find that TIGIT deficiency enhances CD28-mediated PI3K/AKT/mTOR co-stimulatory pathway, which promotes glucose oxidation, citrate production, and increased cytosolic acetyl-CoA levels, ultimately inducing epigenetic reprogramming via histone acetylation. Importantly, pharmacological inhibition of histone acetylation suppresses the differentiation of Th1 and Th17 cells, alleviating muscle inflammation. Thus, our findings reveal a mechanism by which TIGIT directly affects the differentiation of Th1 and Th17 T cells through metabolic‒epigenetic reprogramming, with important implications for treating systemic autoimmune diseases.https://doi.org/10.1038/s41467-025-59786-z |
| spellingShingle | Yimei Lai Shuang Wang Tingting Ren Jia Shi Yichao Qian Shuyi Wang Mianjing Zhou Ryu Watanabe Mengyuan Li Xinyuan Ruan Xin Wang Lili Zhuang Zunfu Ke Niansheng Yang Yuefang Huang Hui Zhang TIGIT deficiency promotes autoreactive CD4+ T-cell responses through a metabolic‒epigenetic mechanism in autoimmune myositis Nature Communications |
| title | TIGIT deficiency promotes autoreactive CD4+ T-cell responses through a metabolic‒epigenetic mechanism in autoimmune myositis |
| title_full | TIGIT deficiency promotes autoreactive CD4+ T-cell responses through a metabolic‒epigenetic mechanism in autoimmune myositis |
| title_fullStr | TIGIT deficiency promotes autoreactive CD4+ T-cell responses through a metabolic‒epigenetic mechanism in autoimmune myositis |
| title_full_unstemmed | TIGIT deficiency promotes autoreactive CD4+ T-cell responses through a metabolic‒epigenetic mechanism in autoimmune myositis |
| title_short | TIGIT deficiency promotes autoreactive CD4+ T-cell responses through a metabolic‒epigenetic mechanism in autoimmune myositis |
| title_sort | tigit deficiency promotes autoreactive cd4 t cell responses through a metabolic epigenetic mechanism in autoimmune myositis |
| url | https://doi.org/10.1038/s41467-025-59786-z |
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