The type III histone deacetylase Sirtl is essential for maintenance of T cell tolerance in mice.
In: Journal of Clinical Investigation, Jg. 119 (2009-10-01), Heft 10, S. 3048-3058
academicJournal
Zugriff:
Although many self-reactive T cells are eliminated by negative selection in the thymus, some of these cells escape into the periphery, where they must be controlled by additional mechanisms. However, the molecular mechanisms underlying peripheral T cell tolerance and its maintenance remain largely undefined. In this study, we report that sirtuin 1 (Sirti), a type III histone deacetylase, negatively regulates T cell activation and plays a major role in clonal T cell anergy in mice. In vivo, we found that loss ofSirtl function resulted in abnormally increased T cell activation and a breakdown of CD4+ T cell tolerance. Conversely, upregulation of Sirti expression led to T cell anergy, in which the activity of the transcription factor AP-1 was substantially diminished. Furthermore, Sirti interacted with and deacetylated c-Jun, yielding an inactive AP-1 factor. In addition, Sirti-deficient mice were unable to maintain T cell tolerance and developed severe experimental allergic encephalomyelitis as well as spontaneous autoimmunity. These findings provide insight into the molecular mechanisms ofT cell activation and anergy, and we suggest that activators ofSirtl may be useful as therapeutic agents for the treatment and/or prevention of autoimmune diseases. [ABSTRACT FROM AUTHOR]
Titel: |
The type III histone deacetylase Sirtl is essential for maintenance of T cell tolerance in mice.
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Autor/in / Beteiligte Person: | Zhang, Jinping ; Lee, Sang-Myeong ; Shannon, Stephen ; Gao, Beixue ; Chen, Weimin ; Chen, An ; Divekar, Rohit ; McBurney, Michael W. ; Braley-Mullen, Helen ; Zaghouani, Habib ; Fang, Deyu |
Zeitschrift: | Journal of Clinical Investigation, Jg. 119 (2009-10-01), Heft 10, S. 3048-3058 |
Veröffentlichung: | 2009 |
Medientyp: | academicJournal |
ISSN: | 0021-9738 (print) |
DOI: | 10.1172/JCI38902 |
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