title: T-bet is a new synergistic meeting point for the BCR and TLR9 signaling cascades.
abstract: The importance of the BCR and TLR9 in autoimmunity and in the production of auto-antibodies is well established but the underlying molecular mechanism still needs to be determined. Here, we aim to characterize the BCR-TLR9 cross-talk by its effect on T-bet, as T-bet is activated and regulated by both receptors and has an important role in class-switching to pathological IgG2a in mice. Using primary mouse B cells, we demonstrate that T-bet expression is synergistically elevated by the cross-talk between the BCR and TLR9. To test the effect of this synergy on IgG2a-switching, the levels of switched B cells were checked by functional tests. We found that BCR costimulation had no additional effect on TLR9-induced IgG2a expression, however the expression of Rad51 was synergistically increased. To check the biological significance of the synergy, we compared T-bet expression in B cells from healthy and collagen-induced arthritis mice but no differences were found. Taken together, we demonstrate here that signaling cascades driven by the BCR and TLR9 have a newly identified meeting point at T-bet. The two cascades act synergistically on T-bet; however additional signals may be needed to induce prolonged functional responses such as class-switch recombination.
authors.affiliation: Department of Immunology, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Dorottya
authors.initials: D
authors.lastname: Kövesdi
authors.forename: Adrienn
authors.initials: A
authors.lastname: Angyal
authors.forename: Krisztina
authors.initials: K
authors.lastname: Huber
authors.forename: Dániel
authors.initials: D
authors.lastname: Szili
authors.forename: Gabriella
authors.initials: G
authors.lastname: Sármay
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D011485:Protein Binding; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D000098815:T-bet Transcription Factor
chemical_list: D007074:Immunoglobulin G; D011947:Receptors, Antigen, B-Cell; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D051217:Toll-Like Receptor 9
keywords: BCR; Signaling; Synergy; T-bet; TLR9