4.6 Article

A Distinct Inhibitory Function for miR-18a in Th17 Cell Differentiation

Journal

JOURNAL OF IMMUNOLOGY
Volume 199, Issue 2, Pages 559-569

Publisher

AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1700170

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Funding

  1. National Institutes of Health [R01HL109102, P01HL107202, U19CA179512, F31HL131361]
  2. Leukemia & Lymphoma Society scholar
  3. National Institute of General Medical Sciences Medical Scientist Training Program Grant [T32GM007618]
  4. National Multiple Sclerosis Society
  5. University of California, San Francisco Program for Breakthrough Biomedical Research-Sandler Foundation
  6. 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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