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miR-146a modulates autoreactive Th17 cell differentiation and regulates organ-specific autoimmunity
Bo Li, … , Mark P. Boldin, Lili Yang
Bo Li, … , Mark P. Boldin, Lili Yang
Published September 5, 2017
Citation Information: J Clin Invest. 2017;127(10):3702-3716. https://doi.org/10.1172/JCI94012.
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Research Article Autoimmunity Immunology Article has an altmetric score of 2

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

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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.

Authors

Bo Li, Xi Wang, In Young Choi, Yu-Chen Wang, Siyuan Liu, Alexander T. Pham, Heesung Moon, Drake J. Smith, Dinesh S. Rao, Mark P. Boldin, Lili Yang

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Figure 3

miR-146a–deficient autoreactive CD4 T cells show altered Th cytokine production.

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miR-146a–deficient autoreactive CD4 T cells show altered Th cytokine pro...
Naive CD4 T cells were sorted from WT and miR-146a–deficient 2D2-Tg mice (denoted as 2D2 and 2D2-KO T cells, respectively) and cultured in vitro for 5 days in the presence of plate-bound anti-CD3 (5 μg/ml) and soluble anti-CD28 (1 μg/ml). Over the time course, cells and cell culture supernatants were collected for analysis. The experiments were repeated more than 3 times, and representative results are presented. (A) qPCR analysis of Th cytokine mRNA expression in 2D2 and 2D2-KO T cells. Data are presented as the mean ± SEM of triplicate cultures. *P < 0.05 and **P < 0.01, by Student’s t test. (B) ELISA analysis of Th cytokine levels in 2D2 and 2D2-KO T cell culture supernatants. Data are presented as the mean ± SEM of triplicate cultures. **P < 0.01, by Student’s t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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