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

Sha, Sha, Pearson, James A ORCID: https://orcid.org/0000-0002-2867-2269, Peng, Jian, Hu, Youjia, Huang, Juan, Xing, Yanpeng, Zhang, Luyao, Zhu, Ying, Zhao, Hongyu, Wong, F. Susan ORCID: https://orcid.org/0000-0002-2812-8845, 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:	27 Nov 2024 13:30
URI:	https://orca.cardiff.ac.uk/id/eprint/137715

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