*Purpose: Interferon-β (IFNβ) is a type I interferon that binds to its receptor (IFNAR) expressed on immune cells. It has known antiviral and pro-inflammatory activity but also is used as an immune modulator. Mechanisms remain unclear.

*Methods: We performed allogenic heart transplants in WT and conditional IFNAR-/- mice with and without CTLA4-Ig and IFNβ, in vitro murine and human Treg induction cultures, and gene expression analyses (RT-PCR) and analyzed Foxp3 expression and acetylation using a proximity ligation assay.

*Results: IFNβ synergized with CTLA4-Ig to prolong graft survival (21 days 50 vs days p<0.01) associated with increased Treg. The prolonged survival required i) recipient Treg and ii) recipient T cell expression of IFNAR (Fig.1A). To address molecular mechanisms we performed mathematical modeling that implicated IFNAR dependent upregulation of the acetyltransferase p300 subsequent Foxp3 acetylation as a mechanism. In vitro Treg induction cultures (murine and human) showed IFNβ augments the percentage of Foxp3+ cells, induces upregulation of p300 (1.33 fold vs. control p<0.05), and increases acetylation of Foxp3 (Fig.1B). Addition of a p300 inhibitor, C646, completely abrogated the effects of IFNβ on Treg induction and Foxp3 acetylation in vitro (Fig. 1B and 1C).

*Conclusions: Our data newly indicate that IFNβ functions to promote Treg-dependent cardiac allograft survival predominantly through enhancing p300-mediated Foxp3 acetylation.

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