Journal
JOURNAL OF IMMUNOLOGY
Volume 199, Issue 2, Pages 559-569Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1700170
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Funding
- National Institutes of Health [R01HL109102, P01HL107202, U19CA179512, F31HL131361]
- Leukemia & Lymphoma Society scholar
- National Institute of General Medical Sciences Medical Scientist Training Program Grant [T32GM007618]
- National Multiple Sclerosis Society
- University of California, San Francisco Program for Breakthrough Biomedical Research-Sandler Foundation
- Deutsche Forschungsgemeinschaft [BA 5132/1-1, SFB 1054]
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Th17 cell responses orchestrate immunity against extracellular pathogens but also underlie autoimmune disease pathogenesis. In this study, we uncovered a distinct and critical role for miR-18a in limiting Th17 cell differentiation. miR-18a was the most dynamically upregulated microRNA of the miR-17-92 cluster in activated T cells. miR-18a deficiency enhanced CCR6(+) RAR-related orphan receptor (ROR) gamma t(+) Th17 cell differentiation in vitro and increased the number of tissue Th17 cells expressing CCR6, ROR gamma t, and IL-17A in airway inflammation models in vivo. Sequence-specific miR-18 inhibitors increased CCR6 and RORgt expression in mouse and human CD4(+) T cells, revealing functional conservation. miR-18a directly targeted Smad4, Hif1a, and Rora, all key transcription factors in the Th17 cell gene-expression program. These findings indicate that activating signals influence the outcome of Th cell differentiation via differential regulation of mature microRNAs within a common cluster.
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