*Purpose: TIP60, a histone/protein acetyltransferase essential for multiple functions in the cell, is involved in Foxp3 acetylation in Treg. Acetylation protects Foxp3 from degradation, and acetylated Foxp3 translocates to the nucleus to activate the immunosuppressive transcriptional program. TIP60 inhibitors have been studied in the context of cancer, but their effect on Treg remains unknown.

*Methods: We performed in vitro murine and human Treg inductions in the presence or absence of three TIP60 inhibitors (NU9056, MG149, and TH1834) and analyzed Foxp3 expression using flow cytometry, and Foxp3 acetylation using a proximity ligation assay.

*Results: In vitro Treg induction cultures (murine and human) showed that TIP60 inhibitors augment the percentage of Foxp3+ cells in a dose-dependent manner (Fig. 1A). To address the molecular mechanisms we performed mathematical modeling that hypothesized an activating effect of TIP60 inhibitors through an increase of Foxp3 acetylation, which we then validated experimentally in our cultures (Fig.1B).

*Conclusions: Our data newly indicate that TIP60 inhibitors have immunomodulatory properties with the potential to prolong allograft survival.

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