Targeting Setdb1 in T cells induces transplant tolerance without compromising antitumor immunity
Abstract Suppressing immune responses promotes allograft survival but also favours tumour progression and recurrence. Selectively suppressing allograft rejection while maintaining or even enhancing antitumor immunity is challenging. Here, we show loss of allograft-related rejection in mice deficient...
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| Language: | English |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58841-z |
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| author | Xiaosheng Tan Xiangli Zhao Zunsong Hu Ding-Sheng Jiang Zhibo Ma Lingjuan Sun Jingzeng Wang Xia Huang Bin Xie Mi Wu Min Ma Cong-Yi Wang Shu Zhang Li Chen Zhishui Chen Gang Chen Peixiang Lan |
| author_facet | Xiaosheng Tan Xiangli Zhao Zunsong Hu Ding-Sheng Jiang Zhibo Ma Lingjuan Sun Jingzeng Wang Xia Huang Bin Xie Mi Wu Min Ma Cong-Yi Wang Shu Zhang Li Chen Zhishui Chen Gang Chen Peixiang Lan |
| author_sort | Xiaosheng Tan |
| collection | DOAJ |
| description | Abstract Suppressing immune responses promotes allograft survival but also favours tumour progression and recurrence. Selectively suppressing allograft rejection while maintaining or even enhancing antitumor immunity is challenging. Here, we show loss of allograft-related rejection in mice deficient in Setdb1, an H3K9 methyltransferase, while antitumor immunity remains intact. RNA sequencing shows that Setdb1-deficiency does not affect T-cell activation or cytokine production but induces an increase in Treg-cell-associated gene expression. Depletion of Treg cells impairs graft acceptance in Setdb1-deficient mice, indicating that the Treg cells promote allograft survival. Surprisingly, Treg cell-specific Setdb1 deficiency does not prolong allograft survival, suggesting that Setdb1 may function prior to Foxp3 induction. Using single-cell RNA sequencing, we find that Setdb1 deficiency induces a new Treg population in the thymus. This subset of Treg cells expresses less IL-1R2 and IL-18R1. Mechanistically, during Treg cell induction, Setdb1 is recruited by transcription factor ATF and altered histone methylation. Our data thus define Setdb1 in T cells as a hub for Treg cell differentiation, in the absence of which suppressing allograft rejection is uncoupled from maintaining antitumor immunity. |
| format | Article |
| id | doaj-art-b4ee70f97f1b449b8e3cfe39b9a976e8 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b4ee70f97f1b449b8e3cfe39b9a976e82025-08-20T01:51:32ZengNature PortfolioNature Communications2041-17232025-05-0116111610.1038/s41467-025-58841-zTargeting Setdb1 in T cells induces transplant tolerance without compromising antitumor immunityXiaosheng Tan0Xiangli Zhao1Zunsong Hu2Ding-Sheng Jiang3Zhibo Ma4Lingjuan Sun5Jingzeng Wang6Xia Huang7Bin Xie8Mi Wu9Min Ma10Cong-Yi Wang11Shu Zhang12Li Chen13Zhishui Chen14Gang Chen15Peixiang Lan16Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Computational and Quantitative Medicine, Beckman Research Institute of City of HopeKey Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical SciencesInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and TechnologySchool of Medicine, South China University of TechnologyDepartment of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Suppressing immune responses promotes allograft survival but also favours tumour progression and recurrence. Selectively suppressing allograft rejection while maintaining or even enhancing antitumor immunity is challenging. Here, we show loss of allograft-related rejection in mice deficient in Setdb1, an H3K9 methyltransferase, while antitumor immunity remains intact. RNA sequencing shows that Setdb1-deficiency does not affect T-cell activation or cytokine production but induces an increase in Treg-cell-associated gene expression. Depletion of Treg cells impairs graft acceptance in Setdb1-deficient mice, indicating that the Treg cells promote allograft survival. Surprisingly, Treg cell-specific Setdb1 deficiency does not prolong allograft survival, suggesting that Setdb1 may function prior to Foxp3 induction. Using single-cell RNA sequencing, we find that Setdb1 deficiency induces a new Treg population in the thymus. This subset of Treg cells expresses less IL-1R2 and IL-18R1. Mechanistically, during Treg cell induction, Setdb1 is recruited by transcription factor ATF and altered histone methylation. Our data thus define Setdb1 in T cells as a hub for Treg cell differentiation, in the absence of which suppressing allograft rejection is uncoupled from maintaining antitumor immunity.https://doi.org/10.1038/s41467-025-58841-z |
| spellingShingle | Xiaosheng Tan Xiangli Zhao Zunsong Hu Ding-Sheng Jiang Zhibo Ma Lingjuan Sun Jingzeng Wang Xia Huang Bin Xie Mi Wu Min Ma Cong-Yi Wang Shu Zhang Li Chen Zhishui Chen Gang Chen Peixiang Lan Targeting Setdb1 in T cells induces transplant tolerance without compromising antitumor immunity Nature Communications |
| title | Targeting Setdb1 in T cells induces transplant tolerance without compromising antitumor immunity |
| title_full | Targeting Setdb1 in T cells induces transplant tolerance without compromising antitumor immunity |
| title_fullStr | Targeting Setdb1 in T cells induces transplant tolerance without compromising antitumor immunity |
| title_full_unstemmed | Targeting Setdb1 in T cells induces transplant tolerance without compromising antitumor immunity |
| title_short | Targeting Setdb1 in T cells induces transplant tolerance without compromising antitumor immunity |
| title_sort | targeting setdb1 in t cells induces transplant tolerance without compromising antitumor immunity |
| url | https://doi.org/10.1038/s41467-025-58841-z |
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