title: Role of TLR in B cell development: signaling through TLR4 promotes B cell maturation and is inhibited by TLR2.
abstract: The role of TLR4 in mature B cell activation is well characterized. However, little is known about TLR4 role in B cell development. Here, we analyzed the effects of TLR4 and TLR2 agonists on B cell development using an in vitro model of B cell maturation. Highly purified B220(+)IgM(-) B cell precursors from normal C57BL/6 mouse were cultured for 72 h, and B cell maturation in the presence of the TLR agonists was evaluated by expression of IgM, IgD, CD23, and AA4. The addition of LPS or lipid A resulted in a marked increase in the percentage of CD23(+) B cells, while Pam3Cys had no effect alone, but inhibited the increase of CD23(+) B cell population induced by lipid A or LPS. The TLR4-induced expression of CD23 is not accompanied by full activation of the lymphocyte, as suggested by the absence of activation Ag CD69. Experiments with TLR2-knockout mice confirmed that the inhibitory effects of Pam3Cys depend on the expression of TLR2. We studied the effects of TLR-agonists on early steps of B cell differentiation by analyzing IL-7 responsiveness and phenotype of early B cell precursors: we found that both lipid A and Pam3Cys impaired IL-7-dependent proliferation; however, while lipid A up-regulates B220 surface marker, consistent with a more mature phenotype of the IgM(-) precursors, Pam3Cys keeps the precursors on a more immature stage. Taken together, our results suggest that TLR4 signaling favors B lymphocyte maturation, whereas TLR2 arrests/retards that process, ascribing new roles for TLRs in B cell physiology.
authors.affiliation: Department of Immunology, Institute of Microbiology, Federal University of Rio de Janeiro, Brazil.
authors.forename: Elize A
authors.initials: EA
authors.lastname: Hayashi
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Alberto
authors.initials: A
authors.lastname: Nobrega
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D003545:Cysteine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006131:Growth Inhibitors / Q000819:agonists / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D016130:Immunophenotyping; D008024:Ligands; D008074:Lipoproteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000819:agonists / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4
chemical_list: D006131:Growth Inhibitors; D008024:Ligands; D008074:Lipoproteins; D011971:Receptors, Immunologic; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C069172:2,3-bis(palmitoyloxy)-2-propyl-1-palmitoylcysteine; D003545:Cysteine