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* Division of Cellular and Molecular Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan;
Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima, Japan; and
Department of Community Health and Medicine, Research Institute International Medical Center of Japan, Tokyo, Japan
Signal transduction pathways regulating NF-
B 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-B 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) β receptor (LtβR) signal induction of nonclassical NF-B activation. However, analysis revealed a TRAF6 role in architecture formation distinct from its role in the early neonatal Lt signaling pathway. LtβR 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.
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1 This work was supported by Grants-in-Aid for Special Coordination Funds for Promoting Science and Technology (to J.-i.I.), a Grant in-Aid for Priority Area Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to T.A. and J.-i.I.) and by The Mochida Memorial Foundation for Medical and Pharmaceutical Research (to T.A.).
2 Address correspondence and reprint requests to Dr. Taishin Akiyama, Division of Cellular and Molecular Biology, Institute of Medical Science, University of Tokyo, Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan; E-mail address: taishin{at}ims.u-tokyo.ac.jp or Dr. Jun-ichiro Inoue, Division of Cellular and Molecular Biology, Institute of Medical Science, University of Tokyo, Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan; E-mail address: jun-i{at}ims.u-tokyo.ac.jp
3 Abbreviations used in this paper: Lt, lymphotoxin; LtβR, Lt β receptor; NIK, NF-B-inducing kinase; TRAF6, TNFR-associated factor 6; RANK, receptor activator of NF-B; RANKL, RANK ligand; TRANCE, TNF-related activation-induced cytokine; FDC, follicular dendritic cell; MAdCAM-1, mucosal addressin cell adhesion molecule-1; PN, postnatal; MEF, mouse embryonic fibroblast; MOMA, anti-monocytes/macrophases; JNK, Jun-N-terminal nucleotide kinase; ER-TR9, anti-mouse SIGN-R1 (clone ER-TR9).
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