title: A TLR9-dependent checkpoint governs B cell responses to DNA-containing antigens.
abstract: Mature B cell pools retain a substantial proportion of polyreactive and self-reactive clonotypes, suggesting that activation checkpoints exist to reduce the initiation of autoreactive B cell responses. Here, we have described a relationship among the B cell receptor (BCR), TLR9, and cytokine signals that regulate B cell responses to DNA-containing antigens. In both mouse and human B cells, BCR ligands that deliver a TLR9 agonist induce an initial proliferative burst that is followed by apoptotic death. The latter mechanism involves p38-dependent G1 cell-cycle arrest and subsequent intrinsic mitochondrial apoptosis and is shared by all preimmune murine B cell subsets and CD27- human B cells. Survival or costimulatory signals rescue B cells from this fate, but the outcome varies depending on the signals involved. B lymphocyte stimulator (BLyS) engenders survival and antibody secretion, whereas CD40 costimulation with IL-21 or IFN-γ promotes a T-bet+ B cell phenotype. Finally, in vivo immunization studies revealed that when protein antigens are conjugated with DNA, the humoral immune response is blunted and acquires features associated with T-bet+ B cell differentiation. We propose that this mechanism integrating BCR, TLR9, and cytokine signals provides a peripheral checkpoint for DNA-containing antigens that, if circumvented by survival and differentiative cues, yields B cells with the autoimmune-associated T-bet+ phenotype.
authors.forename: Vishal J
authors.initials: VJ
authors.lastname: Sindhava
authors.forename: Michael A
authors.initials: MA
authors.lastname: Oropallo
authors.forename: Krishna
authors.initials: K
authors.lastname: Moody
authors.forename: Martin
authors.initials: M
authors.lastname: Naradikian
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Higdon
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.forename: Arpita
authors.initials: A
authors.lastname: Myles
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Green
authors.forename: Kerstin
authors.initials: K
authors.lastname: Nündel
authors.forename: William
authors.initials: W
authors.lastname: Stohl
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Schmidt
authors.forename: Wei
authors.initials: W
authors.lastname: Cao
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dorta-Estremera
authors.forename: Taku
authors.initials: T
authors.lastname: Kambayashi
authors.forename: Ann
authors.initials: A
authors.lastname: Marshak-Rothstein
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cancro
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology*; D053264:B-Cell Activating Factor / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D004247:DNA / Q000276:immunology*; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology; D000098815:T-bet Transcription Factor; D000098546:Interleukin-21
chemical_list: D000941:Antigens; D053264:B-Cell Activating Factor; D019013:CD40 Antigens; C573415:IFNG protein, human; C000611649:IFNG protein, mouse; D007378:Interleukins; D011947:Receptors, Antigen, B-Cell; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C495371:TLR9 protein, human; C505719:TNFSF13B protein, human; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D007371:Interferon-gamma; D004247:DNA; D048051:p38 Mitogen-Activated Protein Kinases; D000098546:Interleukin-21