miR-146a modulates autoreactive Th17 cell differentiation and regulates organ-specific autoimmunity

J Clin Invest. 2017 Oct 2;127(10):3702-3716. doi: 10.1172/JCI94012. Epub 2017 Sep 5.


Autoreactive CD4 T cells that differentiate into pathogenic Th17 cells can trigger autoimmune diseases. Therefore, investigating the regulatory network that modulates Th17 differentiation may yield important therapeutic insights. miR-146a has emerged as a critical modulator of immune reactions, but its role in regulating autoreactive Th17 cells and organ-specific autoimmunity remains largely unknown. Here, we have reported that miR-146a-deficient mice developed more severe experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis (MS). We bred miR-146a-deficient mice with 2D2 T cell receptor-Tg mice to generate 2D2 CD4 T cells that are deficient in miR-146a and specific for myelin oligodendrocyte glycoprotein (MOG), an autoantigen in the EAE model. miR-146a-deficient 2D2 T cells induced more severe EAE and were more prone to differentiate into Th17 cells. Microarray analysis revealed enhancements in IL-6- and IL-21-induced Th17 differentiation pathways in these T cells. Further study showed that miR-146a inhibited the production of autocrine IL-6 and IL-21 in 2D2 T cells, which in turn reduced their Th17 differentiation. Thus, our study identifies miR-146a as an important molecular brake that blocks the autocrine IL-6- and IL-21-induced Th17 differentiation pathways in autoreactive CD4 T cells, highlighting its potential as a therapeutic target for treating autoimmune diseases.

MeSH terms

  • Animals
  • Autocrine Communication / genetics
  • Autocrine Communication / immunology
  • Autoimmunity*
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology
  • Interleukins / genetics
  • Interleukins / immunology
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics
  • MicroRNAs / immunology*
  • Multiple Sclerosis / genetics
  • Multiple Sclerosis / immunology*
  • Myelin-Oligodendrocyte Glycoprotein / genetics
  • Myelin-Oligodendrocyte Glycoprotein / immunology
  • Organ Specificity / genetics
  • Organ Specificity / immunology
  • Th17 Cells / immunology*
  • Th17 Cells / pathology


  • Interleukin-6
  • Interleukins
  • MicroRNAs
  • Mirn146 microRNA, mouse
  • Mog protein, mouse
  • Myelin-Oligodendrocyte Glycoprotein
  • interleukin-6, mouse
  • interleukin-21