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Toll-like receptor 7 deficiency suppresses type 1 diabetes development by modulating B-cell differentiation and function

Huang, Juan, Peng, Jian, Pearson, James Alexander, Efthimiou, Georgios, Hu, Youjia, Tai, Ningwen, Xing, Yanpeng, Zhang, Luyao, Gu, Jianlei, Jiang, Jianping, Zhao, Hongyu, Zhou, Zhiguang, Wong, F. Susan and Wen, Li 2021. Toll-like receptor 7 deficiency suppresses type 1 diabetes development by modulating B-cell differentiation and function. Cellular and Molecular Immunology 10.1038/s41423-020-00590-8

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Abstract

Innate immunity mediated by Toll-like receptors (TLRs), which can recognize pathogen molecular patterns, plays a critical role in type 1 diabetes development. TLR7 is a pattern recognition receptor that senses single-stranded RNAs from viruses and host tissue cells; however, its role in type 1 diabetes development remains unclear. In our study, we discovered that Tlr7-deficient (Tlr7−/−) nonobese diabetic (NOD) mice, a model of human type 1 diabetes, exhibited a significantly delayed onset and reduced incidence of type 1 diabetes compared with Tlr7-sufficient (Tlr7+/+) NOD mice. Mechanistic investigations showed that Tlr7 deficiency significantly altered B-cell differentiation and immunoglobulin production. Moreover, Tlr7−/− NOD B cells were found to suppress diabetogenic CD4+ T-cell responses and protect immunodeficient NOD mice from developing diabetes induced by diabetogenic T cells. In addition, we found that Tlr7 deficiency suppressed the antigen-presenting functions of B cells and inhibited cytotoxic CD8+ T-cell activation by downregulating the expression of both nonclassical and classical MHC class I (MHC-I) molecules on B cells. Our data suggest that TLR7 contributes to type 1 diabetes development by regulating B-cell functions and subsequent interactions with T cells. Therefore, therapeutically targeting TLR7 may prove beneficial for disease protection.

Item Type: Article
Date Type: Published Online
Status: In Press
Schools: Medicine
Additional Information: This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher: Nature Publishing Group
ISSN: 1672-7681
Funders: MRC, JDRF, NIH
Date of First Compliant Deposit: 15 January 2021
Date of Acceptance: 31 October 2020
Last Modified: 19 Jan 2021 10:15
URI: http://orca.cf.ac.uk/id/eprint/137704

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