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TLR9-deficiency in B cells promotes immune tolerance via IL-10 in a type 1 diabetes mouse model

Sha, Sha, Pearson, James A, Peng, Jian, Hu, Youjia, Huang, Juan, Xing, Yanpeng, Zhang, Luyao, Zhu, Ying, Zhao, Hongyu, Wong, F. Susan, Chen, Li and Wen, Li 2021. TLR9-deficiency in B cells promotes immune tolerance via IL-10 in a type 1 diabetes mouse model. Diabetes 70 (2) , pp. 504-515. 10.2337/db20-0373

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Abstract

Toll-like receptor 9 (TLR9) is highly expressed in B cells and B cells are important in the pathogenesis of type 1 diabetes (T1D) development. However, the intrinsic effect of TLR9 in B cells on beta cell autoimmunity is not known. To fill this knowledge gap, we generated non-obese diabetic (NOD) mice with a B cell-specific deficiency of TLR9 (TLR9fl/fl/CD19-Cre+ NOD). The B cell-specific deletion of TLR9 resulted in near complete protection from T1D development. Diabetes protection was accompanied by an increased proportion of IL-10-producing B cells. We also found that TLR9-deficient B cells were hyporesponsive to both innate and adaptive immune-stimuli. This suggested that TLR9 in B cells modulates T1D susceptibility in NOD mice by changing the frequency and function of IL-10-producing B cells. Molecular analysis revealed a network of TLR9 with MMPs, TIMP1 and CD40, all of which are inter-connected with IL-10. Our study has highlighted an important connection of an innate immune molecule in B cells to the immuno-pathogenesis of T1D. Thus, targeting the TLR9 pathway, specifically in B cells, may provide a novel therapeutic strategy for T1D treatment.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: PDF added in accordance with publisher's polices at https://v2.sherpa.ac.uk/id/publication/4056 (accessed 18/01/21)
Publisher: American Diabetes Association
ISSN: 0012-1797
Funders: NIH, ADA, JDRF
Date of First Compliant Deposit: 15 January 2021
Date of Acceptance: 31 October 2020
Last Modified: 10 Feb 2021 04:30
URI: http://orca.cardiff.ac.uk/id/eprint/137715

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