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Immunology and Transplantation

TLR9 Deficiency in B Cells Promotes Immune Tolerance via Interleukin-10 in a Type 1 Diabetes Mouse Model

  1. Sha Sha1,2,3,
  2. James A. Pearson3,
  3. Jian Peng3,
  4. Youjia Hu3,
  5. Juan Huang3,
  6. Yanpeng Xing3,4,
  7. Luyao Zhang3,4,
  8. Ying Zhu5,
  9. Hongyu Zhao5,
  10. F. Susan Wong6,
  11. Li Chen2 and
  12. Li Wen3⇑
  1. 1Department of Nephrology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
  2. 2Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, Shandong, China
  3. 3Section of Endocrinology, School of Medicine, Yale University, New Haven, CT
  4. 4Department of Gastrointestinal Surgery, First Hospital of Jilin University, Changchun, Jilin, China
  5. 5Department of Biostatistics, School of Public Health, Yale University, New Haven, CT
  6. 6Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, U.K.
  1. Corresponding author: Li Wen, li.wen{at}yale.edu
  1. J.A.P. and J.P. contributed equally to the work.

Diabetes 2021 Feb; 70(2): 504-515. https://doi.org/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 β-cell autoimmunity is not known. To fill this knowledge gap, we generated 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 interleukin-10 (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 matrix metalloproteinases, tissue inhibitor of metalloproteinase-1, and CD40, all of which are interconnected with IL-10. Our study has highlighted an important connection of an innate immune molecule in B cells to the immunopathogenesis of T1D. Thus, targeting the TLR9 pathway, specifically in B cells, may provide a novel therapeutic strategy for T1D treatment.

Footnotes

  • This article contains supplementary material online at https://doi.org/10.2337/figshare.13177016.

  • Received April 11, 2020.
  • Accepted November 1, 2020.
  • © 2020 by the American Diabetes Association
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TLR9 Deficiency in B Cells Promotes Immune Tolerance via Interleukin-10 in a Type 1 Diabetes Mouse Model
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
Diabetes Feb 2021, 70 (2) 504-515; DOI: 10.2337/db20-0373

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TLR9 Deficiency in B Cells Promotes Immune Tolerance via Interleukin-10 in a Type 1 Diabetes Mouse Model
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
Diabetes Feb 2021, 70 (2) 504-515; DOI: 10.2337/db20-0373
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