title: BCR and Endosomal TLR Signals Synergize to Increase AID Expression and Establish Central B Cell Tolerance.
abstract: Activation-induced cytidine deaminase (AID) is required to purge autoreactive immature and transitional-1 (immature/T1) B cells at the first tolerance checkpoint, but how AID selectively removes self-reactive B cells is unclear. We now show that B cell antigen receptor (BCR) and endosomal Toll-like receptor (TLR) signals synergize to elicit high levels of AID expression in immature/T1 B cells. This synergy is restricted to ligands for endocytic TLR and requires phospholipase-D activation, endosomal acidification, and MyD88. The first checkpoint is significantly impaired in AID- or MyD88-deficient mice and in mice doubly heterozygous for AID and MyD88, suggesting interaction of these factors in central B cell tolerance. Moreover, administration of chloroquine, an inhibitor of endosomal acidification, results in a failure to remove autoreactive immature/T1 B cells in mice. We propose that a BCR/TLR pathway coordinately establishes central tolerance by hyper-activating AID in immature/T1 B cells that bind ligands for endosomal TLRs.
authors.affiliation: Department of Immunology, Duke University, Durham, NC 27710, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kuraoka
authors.affiliation: Department of Immunology, Duke University, Durham, NC 27710, USA.
authors.forename: Pilar B
authors.initials: PB
authors.lastname: Snowden
authors.affiliation: Department of Immunology, Duke University, Durham, NC 27710, USA.
authors.forename: Takuya
authors.initials: T
authors.lastname: Nojima
authors.affiliation: Human Vaccine Institute, Duke University, Durham, NC 27710, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Verkoczy
authors.affiliation: Department of Immunology, Duke University, Durham, NC 27710, USA; Human Vaccine Institute, Duke University, Durham, NC 27710, USA; Department of Medicine, Duke University, Durham, NC 27710, USA.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.affiliation: Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kitamura
authors.affiliation: Department of Immunology, Duke University, Durham, NC 27710, USA; Human Vaccine Institute, Duke University, Durham, NC 27710, USA. Electronic address: ghkelsoe@duke.edu.
authors.forename: Garnett
authors.initials: G
authors.lastname: Kelsoe
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D003564:Cytidine Deaminase / Q000276:immunology*; D011992:Endosomes / Q000276:immunology; D005260:Female; D007108:Immune Tolerance / Q000276:immunology*; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D010739:Phospholipase D / Q000276:immunology; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology*
chemical_list: D008024:Ligands; D053594:Myeloid Differentiation Factor 88; D011947:Receptors, Antigen, B-Cell; D051193:Toll-Like Receptors; D010739:Phospholipase D; D003564:Cytidine Deaminase
keywords: B cell receptor signaling; B cell tolerance; Toll-like receptor signaling; activation-induced cytidine deaminase; intracellular acidification; myeloid primary response gene (88)