title: Toll-like receptor 9, transmembrane activator and calcium-modulating cyclophilin ligand interactor, and CD40 synergize in causing B-cell activation.
abstract: BACKGROUND
  B cells receive activating signals from T cells through CD40, from microbial DNA through Toll-like receptor (TLR) 9, and from dendritic cells through transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI). TLR9 and CD40 ligation augment TACI-driven B-cell activation, but only the mechanism of synergy between CD40 and TACI has been explored. Synergy between CD40 and TLR9 in B-cell activation is controversial.
  
  
  OBJECTIVE
  We sought to examine the mechanisms by which TLR9 modulates CD40- and TACI-mediated activation of B cells and to determine whether all 3 receptors synergize to activate B cells.
  
  
  METHODS
  Naive murine B cells and human PBMCs were stimulated with combinations of anti-CD40, CpG, and a proliferation inducing ligand in the presence of IL-4. Proliferation was measured by means of tritiated thymidine incorporation. Immunoglobulin production was measured by means of ELISA. Class-switch recombination (CSR) was examined by measuring mRNA for germline transcripts, activation-induced cytidine deaminase (AICDA), and mature immunoglobulin transcripts. Plasma cell differentiation was examined by using syndecan-1/CD138 staining and mRNA expression of B lymphocyte-induced maturation protein 1 (Blimp-1).
  
  
  RESULTS
  TLR9 synergized with CD40 and TACI in driving CSR and inducing IgG(1) and IgE secretion by naive murine B cells and synergized with TACI in driving B-cell proliferation and plasma cell differentiation. All 3 receptors synergized together in driving murine B-cell proliferation, CSR, plasma cell differentiation, and IgG(1) and IgE secretion. TLR9 synergized with CD40 and TACI in driving IgG secretion in IL-4-stimulated human B cells.
  
  
  CONCLUSIONS
  Signals from TLR9, TACI, and CD40 are integrated to promote B-cell activation and differentiation.
authors: Division of Immunology, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Esra
authors: E
authors: Ozcan
authors: Ingrid
authors: I
authors: Rauter
authors: Lilit
authors: L
authors: Garibyan
authors: Stacey R
authors: SR
authors: Dillon
authors: Raif S
authors: RS
authors: Geha
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism*; D002454:Cell Differentiation; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*; D053303:Transmembrane Activator and CAML Interactor Protein / Q000378:metabolism*
chemical_list: D019013:CD40 Antigens; C108467:TNFRSF13B protein, human; D051217:Toll-Like Receptor 9; D053303:Transmembrane Activator and CAML Interactor Protein