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IFN Regulatory Factor-1 Negatively Regulates CD4⁺CD25⁺ Regulatory T Cell Differentiation by Repressing Foxp3 Expression¹

Alessandra Fragale^*, Lucia Gabriele, Emilia Stellacci^*, Paola Borghi, Edvige Perrotti^*, Ramona Ilari^*, Angela Lanciotti^*, Anna Lisa Remoli^*, Massimo Venditti, Filippo Belardelli and Angela Battistini^2,*

^* Department of Infectious, Parasitic and Immunomediated Diseases, and Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy

Regulatory T (Treg) cells are critical in inducing and maintaining tolerance. Despite progress in understanding the basis of immune tolerance, mechanisms and molecules involved in the generation of Treg cells remain poorly understood. IFN regulatory factor (IRF)-1 is a pleiotropic transcription factor implicated in the regulation of various immune processes. In this study, we report that IRF-1 negatively regulates CD4⁺CD25⁺ Treg cell development and function by specifically repressing Foxp3 expression. IRF-1-deficient (IRF-1^–/–) mice showed a selective and marked increase of highly activated and differentiated CD4⁺CD25⁺Foxp3⁺ Treg cells in thymus and in all peripheral lymphoid organs. Furthermore, IRF-1^–/– CD4⁺CD25^– T cells showed extremely high bent to differentiate into CD4⁺CD25⁺Foxp3⁺ Treg cells, whereas restoring IRF-1 expression in IRF-1^–/– CD4⁺CD25^– T cells impaired their differentiation into CD25⁺Foxp3⁺ cells. Functionally, both isolated and TGF-β-induced CD4⁺CD25⁺ Treg cells from IRF-1^–/– mice exhibited more increased suppressive activity than wild-type Treg cells. Such phenotype and functional characteristics were explained at a mechanistic level by the finding that IRF-1 binds a highly conserved IRF consensus element sequence (IRF-E) in the foxp3 gene promoter in vivo and negatively regulates its transcriptional activity. We conclude that IRF-1 is a key negative regulator of CD4⁺CD25⁺ Treg cells through direct repression of Foxp3 expression.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from the Italian AIDS Project, the Italian Ministry of Health, the Istituto Superiore di Sanità-National Institutes of Health Scientific Cooperation agreement and ISS-ACC program 3 (to A.B. and F.B.).

² Address correspondence and reprint requests to Dr. Angela Battistini, Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, viale Regina Elena 299, 00161 Rome, Italy. E-mail address: battist{at}iss.it

³ Abbreviations used in this paper: Treg, regulatory T; inTreg, induced Treg; IRF, IFN regulatory factor; IRF-E, IRF consensus element; DC, dendritic cell; CD62L, CD62 ligand; ChIP, chromatin immunoprecipitation; KO, knockout; WT, wild type.

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				G. Lal and J. S. Bromberg Epigenetic mechanisms of regulation of Foxp3 expression Blood, October 29, 2009; 114(18): 3727 - 3735. [Abstract] [Full Text] [PDF]