B cell-intrinsic TLR signaling inhibits class switching to IgE 4439

Abstract Description Chronic allergic diseases such as allergic asthma are driven by allergen-specific IgE antibodies. B cells produce IgE through class switch recombination (CSR), a process regulated by T cell help and the cytokine, IL-4. Early life exposure to microbial products correlates with lower IgE levels. To model this, we administered a synthetic toll-like receptor 9 (TLR9) agonist, CpG, to mimic microbial DNA exposure in a mouse model of airway hypersensitivity. CpG lowered antigen-specific IgE in the airway and serum. Because B cells express TLRs including TLR9, we examined if direct TLR signaling on B cells inhibits CSR to IgE. We cultured resting mouse B cells with anti-CD40 antibodies and IL-4, with or without various TLR agonists, and observed that all tested agonists reduced IgE CSR by decreasing Iε germline transcription (Iε-GLT), a prerequisite for IgE CSR. Although TLR signaling slightly reduced IL-4 receptor expression at later timepoints, inhibition of Iε-GLT preceded the decrease of IL-4 receptor, suggesting an earlier, independent pathway of inhibition. TLR signaling also drives B cells to differentiate into plasma cells, which cannot undergo CSR. Therefore, we cultured B cells from BLIMP1-reporter mice and found that CpG still inhibited Iε-GLT in BLIMP1-negative cells (non-plasma cells). Notably, we found that TLR signaling upregulated C/EBPβ, an inhibitor of Iε-GLT in B cell lines. We are now investigating whether C/EBPβ mediates TLR-driven reduction of IgE CSR. Funding Sources NIH R01HL165120 NIH R21Al159456 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)