Type I IFN receptor and the B cell antigen receptor regulate TLR7 responses via distinct molecular mechanisms.
Toll-like receptor 7 (TLR7) signals to B cells are critically involved in the innate immune response to microbes, as well as pathogenesis of autoimmune diseases, but the molecular mechanisms that normally regulate these responses are incompletely understood. We previously reported that repeated stimulation through TLR7 induces a state of hyporesponsiveness (TLR tolerance) in both human and mouse B cells, characterized by marked inhibition of particular signaling pathways. BCR signals prevent and overcome TLR7 tolerance. Because optimal responses to TLR7 in B cells require type I IFN, we investigated whether BCR-mediated effects on TLR7 tolerance are mediated by type I IFN receptor (IFNAR) signals. Surprisingly, although BCR-mediated reversal of TLR7 tolerance was IFNAR independent, IFNAR signals alone also blocked TLR7 tolerance, despite enhancing TLR7 expression. Both BCR and IFNAR signals restored the phosphorylation of the transcriptional regulator c-Jun, but only BCR signals blocked the tolerance-mediated inhibition of JNK. Both BCR and IFNAR-mediated regulation was dependent on activation of the PI3K/Akt/mammalian target of rapamycin signaling pathway, indicating a central role for this axis in integrating TLR7, BCR, and IFNAR signals in B cells. These new findings reveal distinct and overlapping signaling mechanisms used by BCR and IFNAR in the regulation of TLR7 tolerance and activation.
Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
Jayakumar S
JS
Poovassery
Gail A
GA
Bishop
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D015153:Blotting, Western; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D053633:Receptor, Interferon alpha-beta / Q000276:immunology* / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000276:immunology* / Q000378:metabolism
D011947:Receptors, Antigen, B-Cell; D051199:Toll-Like Receptor 7; D053633:Receptor, Interferon alpha-beta