title: Two histone/protein acetyltransferases, CBP and p300, are indispensable for Foxp3+ T-regulatory cell development and function.
abstract: T-regulatory (Treg) cells are important to immune homeostasis, and Treg cell deficiency or dysfunction leads to autoimmune disease. A histone/protein acetyltransferase (HAT), p300, was recently found to be important for Treg function and stability, but further insights into the mechanisms by which p300 or other HATs affect Treg biology are needed. Here we show that CBP, a p300 paralog, is also important in controlling Treg function and stability. Thus, while mice with Treg-specific deletion of CBP or p300 developed minimal autoimmune disease, the combined deletion of CBP and p300 led to fatal autoimmunity by 3 to 4 weeks of age. The effects of CBP and p300 deletion on Treg development are dose dependent and involve multiple mechanisms. CBP and p300 cooperate with several key Treg transcription factors that act on the Foxp3 promoter to promote Foxp3 production. CBP and p300 also act on the Foxp3 conserved noncoding sequence 2 (CNS2) region to maintain Treg stability in inflammatory environments by regulating pCREB function and GATA3 expression, respectively. Lastly, CBP and p300 regulate the epigenetic status and function of Foxp3. Our findings provide insights into how HATs orchestrate multiple aspects of Treg development and function and identify overlapping but also discrete activities for p300 and CBP in control of Treg cells.
authors.affiliation: Division of Transplant Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Study of Pediatric Liver Diseases, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Transplant Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Study of Pediatric Liver Diseases, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Liqing
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Transplant Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Study of Pediatric Liver Diseases, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Rongxiang
authors.initials: R
authors.lastname: Han
authors.affiliation: Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Ulf H
authors.initials: UH
authors.lastname: Beier
authors.affiliation: Division of Transplant Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Study of Pediatric Liver Diseases, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Akimova
authors.affiliation: Anatomic Pathology, Children's Hospital of Philadelphia and Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Tricia
authors.initials: T
authors.lastname: Bhatti
authors.affiliation: Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cole
authors.affiliation: Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Brindle
authors.affiliation: Division of Transplant Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Study of Pediatric Liver Diseases, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA whancock@mail.med.upenn.edu.
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000276:immunology; D003092:Colitis / Q000276:immunology* / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D017384:Sequence Deletion; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050990:GATA3 Transcription Factor; D050882:CREB-Binding Protein; D050881:E1A-Associated p300 Protein