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

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

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Department of Microbiology, Immunology and Molecular Genetics.
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research.
Jonsson Comprehensive Cancer Center, the David Geffen School of Medicine.
Molecular Biology Institute, and.
Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.
Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, California, USA.


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.

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