Distinct roles for TLR7 and TLR9 in regulation of B cell signal strength and differentiation (LYM6P.766)

• Published in: The Journal of immunology (1950) 2014-05, Vol.192 (1_Supplement), p.131-131.3
• Main Authors: Nundel, Kerstin, Mande, Purvi, Shaffer, Art, Sindhava, Vishal, Cancro, Michael, Marshak-Rothstein, Ann
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.192.Supp.131.3

BCR signal strength plays a key role in the fate decision of B cells. Strong BCR signals promote plasma cell differentiation and weaker BCR signals drive germinal center B cell fate. Signals through toll-like receptors (TLRs) also influence B cell differentiation, but it is unclear how the BCR and TLR signaling cascades interface to modulate B cell responses and differentiation. To address this question, we used a BCR sdTg mouse model, AM14, in which all mature B cells have a naïve follicular phenotype. The AM14 BCR recognizes IgG2a-bound immune complexes (ICs) and AM14 B cell activation depends on TLR7 and/or TLR9. ICs formed by the anti-nucleosome antibody PL2-3 can activate AM14 B cells through either TLR7 or TLR9, allowing us to dissect signaling pathways unique to each TLR. We find that activation of AM14 TLR7-deficient B cells leads to sustained activation of the NF-κB pathway and p38 phosphorylation, subsequently leading to cell death. In contrast, TLR9-deficient AM14 B cells activated with ICs are unable to sustain the initial NF-κB and p38 signaling response. Intriguingly, these TLR9-deficient AM14 B cells differentiate into short-lived plasmablasts as characterized by increased levels of plasma cell associated proteins such as IRF-4, Blimp-1 and CD138. Plasma cell development is not observed in IC activated TLR7-deficient AM14 B cells. Our results suggest divergent roles for TLR7 and TLR9 in B cell activation and plasma cell differentiation.