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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; Wen, Li

Authors

Juan Huang

Jian Peng

James Alexander Pearson

Youjia Hu

Ningwen Tai

Yanpeng Xing

Luyao Zhang

Jianlei Gu

Jianping Jiang

Hongyu Zhao

Zhiguang Zhou

F. Susan Wong

Li Wen



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.

Citation

Huang, J., Peng, J., Pearson, J. A., Efthimiou, G., Hu, Y., Tai, N., …Wen, L. (in press). Toll-like receptor 7 deficiency suppresses type 1 diabetes development by modulating B-cell differentiation and function. Cellular and Molecular Immunology, https://doi.org/10.1038/s41423-020-00590-8

Journal Article Type Article
Acceptance Date Oct 31, 2020
Online Publication Date Jan 11, 2021
Deposit Date Jan 22, 2021
Publicly Available Date Jan 26, 2021
Journal Cellular & Molecular Immunology
Print ISSN 1672-7681
Electronic ISSN 2042-0226
Publisher University of Science and Technology of China
Peer Reviewed Peer Reviewed
DOI https://doi.org/10.1038/s41423-020-00590-8
Keywords Type 1 diabetes; Toll-like receptor 7; B cell
Public URL https://hull-repository.worktribe.com/output/3698594
Publisher URL https://www.nature.com/articles/s41423-020-00590-8
Additional Information Received: 6 June 2020; Accepted: 31 October 2020; First Online: 11 January 2021; : The authors declare no competing interests.

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Copyright Statement
© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/.





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