title: Sirtuin-1 targeting promotes Foxp3+ T-regulatory cell function and prolongs allograft survival.
abstract: Sirtuin 1 (Sirt1), a class III histone/protein deacetylase, is central to cellular metabolism, stress responses, and aging, but its contributions to various host immune functions have been little investigated. To study the role of Sirt1 in T cell functions, we undertook targeted deletions by mating mice with a floxed Sirt1 gene to mice expressing CD4-cre or Foxp3-cre recombinase, respectively. We found that Sirt1 deletion left conventional T-effector cell activation, proliferation, and cytokine production largely unaltered. However, Sirt1 targeting promoted the expression of Foxp3, a key transcription factor in T-regulatory (Treg) cells, and increased Treg suppressive functions in vitro and in vivo. Consistent with these data, mice with targeted deletions of Sirt1 in either CD4(+) T cells or Foxp3(+) Treg cells exhibited prolonged survival of major histocompatibility complex (MHC)-mismatched cardiac allografts. Allografts in Sirt1-targeted recipients showed long-term preservation of myocardial histology and infiltration by Foxp3(+) Treg cells. Comparable results were seen in wild-type allograft recipients treated with Sirt1 inhibitors, such as EX-527 and splitomicin. Hence, Sirt1 may inhibit Treg functions, and its targeting may have therapeutic value in autoimmunity and transplantation.
authors.affiliation: Division of Nephrology, Department of Pediatrics, The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4318, USA.
authors.forename: Ulf H
authors.initials: UH
authors.lastname: Beier
authors.forename: Liqing
authors.initials: L
authors.lastname: Wang
authors.forename: Tricia R
authors.initials: TR
authors.lastname: Bhatti
authors.forename: Yujie
authors.initials: Y
authors.lastname: Liu
authors.forename: Rongxiang
authors.initials: R
authors.lastname: Han
authors.forename: Guanghui
authors.initials: G
authors.lastname: Ge
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000235:genetics / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology; D019426:Integrases; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation; D009281:Naphthalenes / Q000494:pharmacology; D011753:Pyrones / Q000494:pharmacology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D002227:Carbazoles; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D009281:Naphthalenes; D011753:Pyrones; C444426:splitomicin; C045073:Cre recombinase; D019426:Integrases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1