Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 205, Issue 9, Pages 1983-1991Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20080707
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Funding
- Swiss National Science Foundation [PBBSB-118644]
- Roche Research Foundation
- Freiwillige Akademische Gesellschaft Basel
- American Diabetes Association Mentor-Based Award
- National Institutes of Health [P01 AI35297-15, P30 DK63720, U19 AI056388]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [U19AI056388, P01AI035297] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK063720] Funding Source: NIH RePORTER
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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-specifi c 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.
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