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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.

Author information

1
Department of Microbiology, Immunology and Molecular Genetics.
2
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research.
3
Jonsson Comprehensive Cancer Center, the David Geffen School of Medicine.
4
Molecular Biology Institute, and.
5
Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California, USA.
6
Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, California, USA.

Abstract

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.

PMID:
28872459
PMCID:
PMC5617680
DOI:
10.1172/JCI94012
[Indexed for MEDLINE]
Free PMC Article

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