Graduate Student Thomas Jefferson University Philadelphia, Pennsylvania, United States
Disclosure(s):
Tien Bui: No financial relationships to disclose
Introduction/Rationale: TLR7 signaling is indispensable for the development of spontaneous germinal center (GC) and plasma cell (PC); however, the mechanism that restrains GC and PC formation remain incompletely defined. Here, our goal is to identify the role of E3 ubiquitin ligase Peli1 in the regulation of TLR7-driven spontaneous GC and PC responses.
Methods: Peli1 expression was assessed in activated B cell subsets from SLE-prone Sle1b.Yaa mice, which overexpress TLR7, and in wild-type B cells stimulated with TLR7 agonist R848 in vitro. B cell–intrinsic functions of Peli1 were assessed using global and conditional Peli1-deficient mice. GC and PC responses were assessed by flow cytometry and immunofluorescence imaging of GC architecture. Antibody production was measured by ELISA and metabolic activity was determined by Seahorse analysis, at baseline and following imiquimod treatment.
Results: Peli1 was upregulated in B cells from Sle1b.Yaa mice and in R848-stimulated wild-type B cells. Peli1 deficiency led to increased Tlr7 expression and elevated levels of the NF-kB member, c-Rel. Functionally, loss of Peli1 resulted in enhanced GC B cell and PC responses, increased IgG2c antibody production, and heightened metabolic activity, all of which were further amplified by imiquimod treatment. Conditional deletion of Peli1 in peripheral B cells recapitulated these phenotypes, indicating that Peli1 restrains B cell–intrinsic TLR7-driven immune
Conclusion: We identify the role of Peli-1 in negative regulation of TLR7 expression and TLR7-driven spontaneous GC, PC and IgG2c antibody responses.
