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TLR9-deficiency in B cells Promotes Immune Tolerance via IL-10 in a Type 1 Diabetes Mouse Model

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posted on 05.11.2020, 23:30 by Ada Admin, Sha Sha, James A Pearson, Jian Peng, Youjia Hu, Juan Huang, Yanpeng Xing, Luyao Zhang, Ying Zhu, Hongyu Zhao, F. Susan Wong, Li Chen, Li Wen
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.

Funding

This work was supported by grants from National Institutes of Health (DK092882, DK100500, and P30 DK945735 to LW), by American Diabetes Association (1-14-BS-222 to LW), and by a Juvenile Diabetes Research Foundation Postdoctoral Research Fellowship (PDF-2016-197 to JAP).

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