SIRT1 deacetylates RORγt and enhances Th17 cell generation.
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.
Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158 Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158.
Hyung W
HW
Lim
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
Seung Goo
SG
Kang
Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158.
Jae Kyu
JK
Ryu
Buck Institute for Research on Aging, Novato, CA 94945.
Birgit
B
Schilling
Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158 Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158.
Mingjian
M
Fei
Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158 Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158.
Intelly S
IS
Lee
Buck Institute for Research on Aging, Novato, CA 94945.
Amanuel
A
Kehasse
Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158 Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158.
Kotaro
K
Shirakawa
Laboratory of Viral Genomics, Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.
Masaru
M
Yokoyama
German Cancer Research Center, 69120 Heidelberg, Germany.
Martina
M
Schnölzer
Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158 Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158.
Herbert G
HG
Kasler
Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158 Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158.
Hye-Sook
HS
Kwon
Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158 Buck Institute for Research on Aging, Novato, CA 94945.
Bradford W
BW
Gibson
Laboratory of Viral Genomics, Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.
Hironori
H
Sato
Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158 Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158.
Katerina
K
Akassoglou
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
Changchun
C
Xiao
Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, The Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016 Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, The Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016.
Dan R
DR
Littman
Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158 Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158 everdin@gladstone.ucsf.edu melanie.ott@gladstone.ucsf.edu.
Melanie
M
Ott
Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158 Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158 everdin@gladstone.ucsf.edu melanie.ott@gladstone.ucsf.edu.
Eric
E
Verdin
D000107:Acetylation; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000276:immunology*; D056564:Sirtuin 1 / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology*
D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1