The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20080707
The Journal of Experimental Medicine, Vol. 205, No. 9, 1983-1991
The Rockefeller University Press, 0022-1007 $30.00
© Zhou et al.
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BRIEF DEFINITIVE REPORT

 Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity

Xuyu Zhou1, Lukas T. Jeker1, Brian T. Fife1, Shirley Zhu1, Mark S. Anderson1,2, Michael T. McManus1,3, and Jeffrey A. Bluestone1,2,3

1 Diabetes Center, 2 Department of Medicine, and 3 Department of Microbiology and Immunology, University of California, San Francisco (UCSF), San Francisco, CA 94143

CORRESPONDENCE Jeffrey A. Bluestone: jbluest{at}diabetes.ucsf.edu

A new regulatory T (T reg) cell–specific, FoxP3-GFP-hCre bacterial artificial chromosome transgenic mouse was crossed to a conditional Dicer knockout (KO) mouse strain to analyze the role of microRNAs (miRNAs) in the development and function of T reg cells. Although thymic T reg cells developed normally in this setting, the cells showed evidence of altered differentiation and dysfunction in the periphery. Dicer-deficient T reg lineage cells failed to remain stable, as a subset of cells down-regulated the T reg cell–specific transcription factor FoxP3, whereas the majority expressed altered levels of multiple genes and proteins (including Neuropilin 1, glucocorticoid-induced tumor necrosis factor receptor, and cytotoxic T lymphocyte antigen 4) associated with the T reg cell fingerprint. In fact, a significant percentage of the T reg lineage cells took on a T helper cell memory phenotype including increased levels of CD127, interleukin 4, and interferon {gamma}. Importantly, Dicer-deficient T reg cells lost suppression activity in vivo; the mice rapidly developed fatal systemic autoimmune disease resembling the FoxP3 KO phenotype. These results support a central role for miRNAs in maintaining the stability of differentiated T reg cell function in vivo and homeostasis of the adaptive immune system.

© 2008 Zhou et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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