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VISA is required for B cell expression of TLR7.

B cells play a critical role in the initialization and development of the systemic lupus erythematosus that is dependent on the expression of the endosomal ssRNA receptor TLR7. Previous studies have established that B cell expression of TLR7 is controlled by the type I IFN secreted by plasmacytoid dendritic cells. In this article, we report that VISA, also known as MAVS, IPS-1, and CardIf, essential for RIG-I/MDA5-mediated signaling following sensing of cytosolic RNA, regulate B cell expression of TLR7 and CD23. We found that B cells from a VISA(-/-) mouse express reduced TLR7 but normal basal levels of type I IFN. We also show that although IFN-β and TLR7 agonists synergize to promote TLR7 expression in VISA(-/-) B cells, they do not fully complement the defect seen in VISA(-/-) cells. Cell transfer experiments revealed that the observed effects of VISA(-/-) are B cell intrinsic. The reduced TLR7 expression in B cells is correlated with impaired TLR7 agonist-induced upregulation of activation markers CD69 and CD86, cell proliferation, production of IFN-α, TNF, and IL-12, and NF-κB activation. Finally, studies indicate that genetic background may influence the observed phenotype of our VISA(-/-) mice, because VISA(-/-) B cells differ in CD23 and TLR7 expression when on C57BL/6 versus 129Sv-C57BL/6 background. Thus, our findings suggest an unexpected link between VISA-mediated cytosolic RLR signaling and autoimmunity.

Pubmed ID: 22105994

Authors

  • Xu LG
  • Jin L
  • Zhang BC
  • Akerlund LJ
  • Shu HB
  • Cambier JC

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Data

January 1, 2012

Associated Grants

  • Agency: NIAID NIH HHS, Id: P01 AI022295
  • Agency: NIAID NIH HHS, Id: P01 AI022295-22
  • Agency: NIAID NIH HHS, Id: P01AI022295022
  • Agency: NIAID NIH HHS, Id: R01 AI062739
  • Agency: NIAID NIH HHS, Id: R01 AI062739-05
  • Agency: NIAID NIH HHS, Id: R01 AI062739-05S1
  • Agency: NIAID NIH HHS, Id: R01 AI062739-05S2
  • Agency: NIAID NIH HHS, Id: R01AI062739-05
  • Agency: NIAID NIH HHS, Id: R01AI062739-05S1
  • Agency: NIAID NIH HHS, Id: R01AI062739-05S2

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antigens, CD
  • Autoimmunity
  • B-Lymphocytes
  • Cell Proliferation
  • Cytokines
  • Gene Expression Regulation
  • Membrane Glycoproteins
  • Mice
  • Mice, Knockout
  • Signal Transduction
  • Toll-Like Receptor 7