Complementary Roles of GCN5 and PCAF in Foxp3+ T-Regulatory Cells

Cancers

Liqing Wang¹  Tatiana Akimova¹  WayneW. Hancock¹  SharonY. R. Dent²  UlfH. Beier²  Chunrong Bao²  Yujie Liu³  PhilipA. Cole³  Rongxiang Han³ 

[1] Biesecker Center for Study of Pediatric Liver Diseases, Children’s Hospital of Philadelphia, and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;;Laboratory Medicine &;Transplant Immunology, Department of Pathology &

关键词: acetyltransferase;    Treg cells;    epigenetics;    transplantation;    autoimmunity;    anti-tumor immunity;    acetylation;    chromatin;   

DOI  :  10.3390/cancers11040554

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown