Sirtuin-1 targeting promotes Foxp3+ T-regulatory cell function and prolongs allograft survival

Mol Cell Biol. 2011 Mar;31(5):1022-9. doi: 10.1128/MCB.01206-10. Epub 2011 Jan 3.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carbazoles / pharmacology
  • Forkhead Transcription Factors / immunology
  • Graft Rejection / immunology
  • Graft Survival / genetics
  • Graft Survival / immunology*
  • Heart Transplantation / immunology
  • Integrases
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mutation
  • Naphthalenes / pharmacology
  • Pyrones / pharmacology
  • Sirtuin 1 / antagonists & inhibitors
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*


  • 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide
  • Carbazoles
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Naphthalenes
  • Pyrones
  • splitomicin
  • Cre recombinase
  • Integrases
  • Sirt1 protein, mouse
  • Sirtuin 1