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

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.