Targeting Setdb1 in T cells induces transplant tolerance without compromising antitumor immunity

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.

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Publication Details

Journal
Nature Communications
Published
2025-05-15
DOI
https://doi.org/10.1038/s41467-025-58841-z
Citations
7
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
5.58

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article

Targeting Setdb1 in T cells induces transplant tolerance without compromising antitumor immunity

Peixiang Lan, Li Chen, Cong‐Yi Wang, Lingjuan Sun et al.
7 citations
Nature Communications
Immune Cell Function and Interaction
5.58
article

Targeting Setdb1 in T cells induces transplant tolerance without compromising antitumor immunity

Peixiang Lan, Li Chen, Cong‐Yi Wang, Lingjuan Sun, Zhishui Chen, Mi Wu, Xiaosheng Tan, Jingzeng Wang, Xiangli Zhao, Zunsong Hu, Gang Chen, Shu Zhang, Min Ma, Ding‐Sheng Jiang, Zhibo Ma, Bin Xie, Xia Huang
article en
7 citations

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.

Nature CommunicationsVol. 16(1)
City Of Hope National Medical Center (US), Ministry of Education of the People's Republic of China (CN), Chinese Academy of Sciences (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), City of Hope (US), Tongji Hospital (CN), Beckman Research Institute, Huazhong University of Science and Technology (CN), South China University of Technology (CN)
National Natural Science Foundation of China, Chinese Academy of Medical Sciences
Zero hunger
Openalex Percentile: Top 4%
Immune Cell Function and Interaction
5.58
DOIOpen Access PDFOpenAlex
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