The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.
Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization
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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Citations
Cites
Control of Regulatory T Cell Development by the Transcription Factor Foxp3
Hori, S., Nomura, T., & Sakaguchi, S. (2003) · Science · doi:10.1126/science.1079490 · Cited by 8,187
Foxp3 programs the development and function of CD4+CD25+ regulatory T cells
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Cancer chemopreventive activity of resveratrol, a natural product derived from grapes
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Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes
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Transient expression of FOXP3 in human activated nonregulatory CD4 + T cells
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Deacetylase inhibition promotes the generation and function of regulatory T cells
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Cited by
Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation
Arpaia, N., Campbell, C., Fan, X., Dikiy, S., van der Veeken, J., deRoos, P., Liu, H., Cross, J. R., Pfeffer, K., Coffer, P. J., et al. (2013) · Nature · doi:10.1038/nature12726 · Cited by 4,838
Self-citationNAD + in aging, metabolism, and neurodegeneration
Verdin, E. (2015) · Science · doi:10.1126/science.aac4854 · Cited by 1,319
Regulatory T cells in autoimmune disease
Dominguez-Villar, M., & Hafler, D. A. (2018) · Nature Immunology · doi:10.1038/s41590-018-0120-4 · Cited by 713
The regulation of immune tolerance by FOXP3
Lu, L., Barbi, J., & Pan, F. (2017) · Nature Reviews Immunology · doi:10.1038/nri.2017.75 · Cited by 580
Histone deacetylases as regulators of inflammation and immunity
Shakespear, M. R., Halili, M. A., Irvine, K. M., Fairlie, D. P., & Sweet, M. J. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.04.001 · Cited by 546
Metadata
- Authors
- van Loosdregt, J., Vercoulen, Y., Guichelaar, T., Gent, Y. Y. J., Beekman, J. M., van Beekum, O., Brenkman, A. B., Hijnen, D.-J., Mutis, T., Kalkhoven, E., Prakken, B. J., & Coffer, P. J.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2010-02-04
- Volume
- 115
- Issue
- 5
- Pages
- 965-974
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2019918813
- Cited by
- 388
- References
- 38
- FWCI
- 7.38
- Type
- journal article
- Language
- en
- Open access
- closed
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- van Loosdregt, J., Vercoulen, Y., Guichelaar, T., Gent, Y. Y. J., Beekman, J. M., van Beekum, O., Brenkman, A. B., Hijnen, D.-J., Mutis, T., Kalkhoven, E., Prakken, B. J., & Coffer, P. J. (2010). Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization. Blood. https://doi.org/10.1182/blood-2009-02-207118
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