Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization

J Van Loosdregt, Y Vercoulen… - Blood, The Journal …, 2010 - ashpublications.org
J Van Loosdregt, Y Vercoulen, T Guichelaar, YYJ Gent, JM Beekman, O Van Beekum…
Blood, The Journal of the American Society of Hematology, 2010ashpublications.org
Regulatory T cells (Tregs) are a specific subset of lymphocytes that are critical for the
maintenance of self-tolerance. Expression levels of the transcription factor Foxp3 have been
causally associated with Treg differentiation and function. Recent studies show that Foxp3
can also be transiently expressed in effector T cells; however, stable Foxp3 expression is
required for development of a functional Treg suppressor phenotype. Here, we demonstrate
that Foxp3 is acetylated, and this can be reciprocally regulated by the histone …
Abstract
Regulatory T cells (Tregs) are a specific subset of lymphocytes that are critical for the maintenance of self-tolerance. Expression levels of the transcription factor Foxp3 have been causally associated with Treg differentiation and function. Recent studies show that Foxp3 can also be transiently expressed in effector T cells; however, stable Foxp3 expression is required for development of a functional Treg suppressor phenotype. Here, we demonstrate that Foxp3 is acetylated, and this can be reciprocally regulated by the histone acetyltransferase p300 and the histone deacetylase SIRT1. Hyperacetylation of Foxp3 prevented polyubiquitination and proteasomal degradation, therefore dramatically increasing stable Foxp3 protein levels. Moreover, using mouse splenocytes, human peripheral blood mononuclear cells, T cell clones, and skin-derived T cells, we demonstrate that treatment with histone deacetylase inhibitors resulted in significantly increased numbers of functional Treg cells. Taken together, our data demonstrate that modulation of the acetylation state of Foxp3 provides a novel molecular mechanism for assuring rapid temporal control of Foxp3 levels in T cells, thereby regulating Treg numbers and functionality. Manipulating Foxp3 acetylation levels could therefore provide a new therapeutic strategy to control inappropriate (auto)immune responses.
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