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: | 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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