Previous studies showed that a pharmacological SIRT1 activator suppressed proliferation of and cytokine production by T cells, which suggested that SIRT1 might be a negative regulator of T cell activation. To test this, the authors used Sirt1−/− mice. Although T cell development was normal in these mice, stimulation of Sirt1−/− T cells in vitro and in vivo led to greater proliferation and more interleukin-2 production than stimulation of T cells from Sirt1+/− littermates. Interestingly, in vitro stimulation of Sirt1−/− T cells with CD3-specific antibodies without co-stimulation, which induces anergy in wild-type T cells, resulted in full T cell activation, suggesting that SIRT1 might function as an anergic factor. A four- to fivefold increase in Sirt1 expression levels in anergic wild-type T cells compared with naive wild-type T cells provided further evidence of a role for SIRT1 in anergy.
To determine whether SIRT1 was required to maintain T cell peripheral tolerance to self antigen in vivo, Sirt1−/− and Sirt1+/− mice were immunized with myelin oligodendrocyte glycoprotein 35–55 peptide to induce experimental autoimmune encephalomyelitis (EAE). More Sirt1−/− mice showed signs of EAE after immunization, disease onset occurred earlier and the average clinical score was higher than for the Sirt1+/− mice. So, the authors concluded that SIRT1 prevented activation of autoreactive T cells and the development of autoimmunity.
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