Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity

Xuyu Zhou, Lukas T. Jeker, Brian T. Fife, Shirley Zhu, Mark S. Anderson, Michael T. McManus, Jeffrey A. Bluestone

Research output: Contribution to journalArticlepeer-review

403 Scopus citations

Abstract

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 γ. Importantly, Dicerdeficient 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.

Original languageEnglish (US)
Pages (from-to)1983-1991
Number of pages9
JournalJournal of Experimental Medicine
Volume205
Issue number9
DOIs
StatePublished - Sep 1 2008

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