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Targeting Setdb1 in T Cells Induces Transplant Tolerance without Compromising Antitumor Immunity

ABSTRACT: Suppressing immune responses promotes allograft survival but also favors tumor progression and recurrence. How to selectively suppress allograft rejection while maintaining or even enhancing antitumor immunity is challenging. Here, we found mice deficient in Setdb1, an H3K9 methyltransferase, retained allograft-related rejection but exhibited retentive antitumor immunity. RNA-Seq showed that Setdb1 deficiency did not affect T-cell activation or cytokine production, but it induced an increase in regulatory T (Treg) cell-associated gene expression. Treg cell depletion impaired graft acceptance in Setdb1-deficient mice, indicating that the Treg cells promoted allograft survival. Surprisingly, Treg cell-specific Setdb1 deficiency did not prolong allograft survival, suggesting that Setdb1 may function prior to Foxp3 induction. Using single-cell RNA sequencing, we found that Setdb1 deficiency induced a new Treg population in the thymus. This subset of Treg cells expressed less IL-1R2 and IL-18R1. Mechanistically, during Treg cell induction, Setdb1 was recruited by transcription factor ATF and modified histone methylation. Our data define Setdb1 in T cells as a target for suppressing allograft rejection while maintaining antitumor immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE288264 | GEO | 2025/03/17

REPOSITORIES: GEO

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Project description:CONTEXT Slowly progressive chronic tubulo-interstitial damage jeopardizes long-term renal allograft survival. Both immune and non-immune mechanisms are thought to contribute, but the most promising targets for timely intervention have not been identified. OBJECTIVE In the current study we seek to determine the driving force behind progressive histological damage of renal allografts, without the interference of donor pathology, delayed graft function and acute graft rejection. DESIGN We used microarrays to examine whole genome expression profiles in renal allograft protocol biopsies, and analyzed the correlation between gene expression and the histological appearance over time. The gene expression profiles in these protocol biopsies were then compared with gene expression of biopsies with acute T-cell mediated rejection. PATIENTS Human renal allograft biopsies (N=120) were included: 96 rejection-free protocol biopsies and 24 biopsies with T-cell mediated acute rejection. RESULTS In this highly cross-validated study, we demonstrate the significant association of established, ongoing and future chronic histological damage with regulation of adaptive immune gene expression (T-cell and B-cell transcript sets) and innate immune response gene expression (dendritic cell, NK-cell, mast cell and granulocyte transcripts). We demonstrate the ability of gene expression analysis to perform as a quantitative marker for ongoing inflammation with a wide dynamic range: from subtle subhistological inflammation prior to development of chronic damage, over moderate subclinical inflammation associated with chronic histological damage, to marked inflammation of Banff-grade acute T-cell mediated rejection. CONCLUSION Progressive chronic histological damage after kidney transplantation is associated with significant regulation of both innate and adaptive immune responses, months before the histological lesions appear. This study therefore corroborates the hypothesis that quantitative inflammation below the diagnostic threshold of classic T-cell or antibody-mediated rejection is associated with early subclinical stages of progressive renal allograft damage. We used microarrays to examine whole genome expression profiles in renal allograft protocol biopsies, and analyzed the correlation between gene expression and the histological appearance over time. The gene expression profiles in these protocol biopsies were then compared with gene expression of biopsies with acute T-cell mediated rejection. Human renal allograft biopsies (N=120) were included: 96 rejection-free protocol biopsies and 24 biopsies with T-cell mediated acute rejection.

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Targeting Setdb1 in T Cells Induces Transplant Tolerance without Compromising Antitumor Immunity

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