Abstract
Functions of the GCN5-related N-acetyltransferase (GNAT) family of histone/protein acetyltransferases (HATs) in Foxp3+ T-regulatory (Treg) cells are unexplored, despite the general importance of these enzymes in cell biology. We now show that two prototypical GNAT family members, GCN5 (general control nonrepressed-protein 5, lysine acetyltransferase (KAT)2a) and p300/CBP-associated factor (p300/CBP-associated factor (PCAF), Kat2b) contribute to Treg functions through partially distinct and partially overlapping mechanisms. Deletion of Gcn5 or PCAF did not affect Treg development or suppressive function in vitro, but did affect inducible Treg (iTreg) development, and in vivo, abrogated Treg-dependent allograft survival. Contrasting effects were seen upon targeting of each HAT in all T cells; mice lacking GCN5 showed prolonged allograft survival, suggesting this HAT might be a target for epigenetic therapy in allograft recipients, whereas transplants in mice lacking PCAF underwent acute allograft rejection. PCAF deletion also enhanced anti-tumor immunity in immunocompetent mice. Dual deletion of GCN5 and PCAF led to decreased Treg stability and numbers in peripheral lymphoid tissues, and mice succumbed to severe autoimmunity by 3–4 weeks of life. These data indicate that HATs of the GNAT family have contributions to Treg function that cannot be replaced by the functions of previously characterized Treg HATs (CBP, p300, and Tip60), and may be useful targets in immuno-oncology.
Highlights
The development of T-regulatory (Treg) cells that play essential roles in immune tolerance and homeostasis requires both Foxp3 expression and establishment of a specific pattern of CpG hypomethylation [1,2]
Foxp3cre mice, or in all T cells by mating with CD4cre mice, whereas PCAF studies used mice with global gene deletion (PCAF−/−), and studies of dual-targeted mice were focused on Treg cells (Foxp3cre Gcn5fl/fl /PCAF−/− mice)
GCN5 deletion in CD4+CD25− Teff cells did not affect PCAF expression level compared to WT T cells (Figure 1F), but when cultured for 3 days using standard conditions that promote induced Treg (iTreg) development [6], GCN5 deletion had no significant effect on iTreg production in vitro (Figure 1G, Figure S1C)
Summary
The development of T-regulatory (Treg) cells that play essential roles in immune tolerance and homeostasis requires both Foxp expression and establishment of a specific pattern of CpG hypomethylation [1,2]. Each process has a distinct role in establishing Treg-specific gene expression. Foxp represses expression of several key molecules, such as IL-2, IFN-γ and Zap, whereas Treg cell-specific CpG hypomethylation enhances Ikzf and Ikzf expression [3,4]. Foxp expression is required to maintain both Treg populations. Complementary in vitro and in vivo studies show Foxp is regulated by multiple post-translational modifications, including acetylation, ubiquitination, and phosphorylation that affect Foxp DNA binding ability and protein stability, and regulate Treg stability, proliferation, and suppressive function [6,7,8,9,10,11]
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