SIRT1 deacetylates RORγt and enhances Th17 cell generation

J Exp Med. 2015 May 4;212(5):607-17. doi: 10.1084/jem.20132378. Epub 2015 Apr 27.


The balance of effector and regulatory T cell function, dependent on multiple signals and epigenetic regulators, is critical to immune self-tolerance. Dysregulation of T helper 17 (Th17) effector cells is associated with multiple autoimmune diseases, including multiple sclerosis. Here, we report that Sirtuin 1 (SIRT1), a protein deacetylase previously reported to have an antiinflammatory function, in fact promotes autoimmunity by deacetylating RORγt, the signature transcription factor of Th17 cells. SIRT1 increases RORγt transcriptional activity, enhancing Th17 cell generation and function. Both T cell-specific Sirt1 deletion and treatment with pharmacologic SIRT1 inhibitors suppress Th17 differentiation and are protective in a mouse model of multiple sclerosis. Moreover, analysis of infiltrating cell populations during disease induction in mixed hematopoietic chimeras shows a marked bias against Sirt1-deficient Th17 cells. These findings reveal an unexpected proinflammatory role of SIRT1 and, importantly, support the possible therapeutic use of SIRT1 inhibitors against autoimmunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Disease Models, Animal
  • Mice
  • Mice, Knockout
  • Multiple Sclerosis / genetics
  • Multiple Sclerosis / immunology*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology*
  • Sirtuin 1 / genetics
  • Sirtuin 1 / immunology*
  • Th17 Cells / immunology*
  • Th17 Cells / pathology
  • Transcription, Genetic / genetics
  • Transcription, Genetic / immunology*


  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Sirt1 protein, mouse
  • Sirtuin 1

Associated data

  • PDB/2NLL