title: Developmental stage-dependent collaboration between the TNF receptor-associated factor 6 and lymphotoxin pathways for B cell follicle organization in secondary lymphoid organs.
abstract: Signal transduction pathways regulating NF-kappaB activation essential for microenvironment formation in secondary lymphoid organs remain to be determined. We investigated the effect of a deficiency of TNFR-associated factor 6 (TRAF6), which activates the classical NF-kappaB pathway, in splenic microenvironment formation. Two-week-old TRAF6-deficient mice showed severe defects in B cell follicle and marginal zone formation, similar to mutant mice defective in lymphotoxin (Lt) beta receptor (LtbetaR) signal induction of nonclassical NF-kappaB activation. However, analysis revealed a TRAF6 role in architecture formation distinct from its role in the early neonatal Lt signaling pathway. LtbetaR signal was essential for primary B cell cluster formation with initial differentiation of follicular dendritic cells (FDCs) in neonatal mice. In contrast, TRAF6 was dispensable for progression to this stage but was required for converting B cell clusters to B cell follicles and maintaining FDCs through to later stages. Fetal liver transfer experiments suggested that TRAF6 in radiation-resistant cells is responsible for follicle formation. Despite FDC-specific surface marker expression, FDCs in neonatal TRAF6-deficient mice had lost the capability to express CXCL13. These data suggest that developmentally regulated activation of TRAF6 in FDCs is required for inducing CXCL13 expression to maintain B cell follicles.
authors.affiliation: Division of Cellular and Molecular Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Junwen
authors.initials: J
authors.lastname: Qin
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Konno
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ohshima
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yanai
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Motegi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shimo
authors.forename: Fumiko
authors.initials: F
authors.lastname: Hirota
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takaki
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Inoue
authors.forename: Taishin
authors.initials: T
authors.lastname: Akiyama
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000276:immunology; D002454:Cell Differentiation; D054382:Chemokine CXCL13 / Q000096:biosynthesis / Q000276:immunology*; D020566:Dendritic Cells, Follicular / Q000276:immunology* / Q000378:metabolism; D008099:Liver / Q000254:growth & development / Q000276:immunology / Q000378:metabolism; D053259:Lymphotoxin beta Receptor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053308:Lymphotoxin-beta / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000254:growth & development / Q000276:immunology* / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D054382:Chemokine CXCL13; C486386:Cxcl13 protein, mouse; C505887:Ltb protein, mouse; D053259:Lymphotoxin beta Receptor; D053308:Lymphotoxin-beta; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6