The type III histone deacetylase Sirt1 is essential for maintenance of T cell tolerance in mice

Abstract

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 (Sirt1), 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 of Sirt1 function resulted in abnormally increased T cell activation and a breakdown of CD4 + T cell tolerance. Conversely, upregulation of Sirt1 expression led to T cell anergy, in which the activity of the transcription factor AP-1 was substantially diminished. Furthermore, Sirt1 interacted with and deacetylated c-Jun, yielding an inactive AP-1 factor. In addition, Sirt1-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 of T cell activation and anergy, and we suggest that activators of Sirt1 may be useful as therapeutic agents for the treatment and/or prevention of autoimmune diseases.

Basic leucine zipper transcription factor, ATF-like (BATF) regulates epigenetically and energetically effector CD8 T-cell differentiation via Sirt1 expression

“…S6B), suggesting that Sirt1 inhibition promotes the survival of activated T cells. These results are consistent with the finding that loss of Sirt1 increases T-cell activation (26). Treatment with the Sirt1 inhibitors, but not with NAD + , increased the viability of Batf +/+ CD8 T cells stimulated with anti-CD3/CD28+IL-12 ( Fig.…”

“…Although Sirt1 has been reported to modulate T-cell activation (26), the administration of Sirt1 inhibitors or activators is associated with many side effects because Sirt1 is expressed in many cell types. Because BATF expression is restricted to activated lymphocytes, BATF may be a promising therapeutic target to control effector T-cell generation for vaccine development and immunotherapies.…”

Roles of Reactive Oxygen Species in Rheumatoid Arthritis Pathogenesis

“…SIRT1 is required to maintain T-cell tolerance [61]. And the lack of SIRT1 resulted in hyperacetylation of c-Jun and the breakdown of T cell tolerance [62]. Therefore, the decreased activity of SIRT1 in aged people and RA patients may result in the activation of autoimmune T cells.…”

Sirtuins and inflammation: Friends or foes?

“…In a recent study, Gao and coworkers showed that c-Jun transcriptional activity can be downregulated by SIRT1 in vitro [37]. A second study rapidly followed, showing that c-Jun is actively deacetylated by SIRT1 in vivo [38], while a third team reported that both the subunits c-Jun and c-Fos are targeted by SIRT1 [39]. These events play a major role in regulating the function of several immune cells.…”

“…In T lymphocytes, AP-1 deacetylation by SIRT1 underlies T cell anergy and permits peripheral tolerance, preventing uncontrolled T cell proliferation and cytokine production [38]. As a consequence, SIRT1 -/-mice display an increased T cell responsiveness in vitro and Page 10 of 28 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 10 are predisposed to develop autoimmune disorders, a conclusion further confirmed by an independent study [40].…”