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TNF Receptor-Associated Factor 2-Dependent Canonical Pathway Is Crucial for the Development of Peyer’s Patches¹

Jiang-Hu Piao^*, Hisahiro Yoshida, Wen-Chen Yeh, Takahiro Doi, Xin Xue^*, Hideo Yagita^*, Ko Okumura^* and Hiroyasu Nakano^2,*

^* Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan; Immunogenetics, Research Center for Allergy & Immunology, RIKEN, Yokohama, Japan; Campbell Family Institute for Breast Cancer Research, University Health Network, University of Toronto, Toronto, Ontario, Canada; and Subteam for BioResponse Integration, RIKEN, BioResource Center, Ibaraki, Japan

Activation of the noncanonical pathway through the interaction of lymphotoxin (LT)-₁₂ and LT-R is essential for the development of secondary lymphoid organs including lymph nodes (LN) and Peyer’s patches (PP). Although TNFR-associated factor (TRAF) 2 and TRAF5 were identified as signal transducers for the LT-R, roles for TRAF2 and TRAF5 in the development of secondary lymphoid organs remain obscure. In this study, we show that PP but not mesenteric LN development is severely impaired in traf2^–/– and traf2^–/–traf5^–/– mice. Development of VCAM-1⁺ and ICAM-1⁺ mesenchymal cells and expression of CXCL13, a crucial chemokine for the development of PP, are severely impaired in PP anlagen in the intestines of traf2^–/– mice. Surprisingly, TNF- stimulation potently up-regulates cxcl13 mRNA expression in wild-type murine embryonic fibroblasts, which is impaired in traf2^–/– and relA^–/– murine embryonic fibroblasts. Moreover, RelA is recruited to the promoter of cxcl13 gene upon TNF- stimulation and PP development is impaired in TNFR type 1 (tnfr1)^–/– mice. These results underscore a crucial role for the TNFR1-TRAF2-RelA-dependent canonical pathway in the development of PP through up-regulation of cxcl13 mRNA.

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¹ This work was supported in part by grants-in-aid for 21st Century Centers of Excellence Research, Scientific Research (B) from the Japan Society for the Promotion of Science, and grants from the Takeda Science Foundation and the Tokyo Biochemical Research Foundation by a grant from the Human Frontier Science Program, and by a High Technology Research Center Grant from the Ministry of Education, Culture, Sport, Science and Technology, Japan.

² Address correspondence and reprint requests to Dr. Hiroyasu Nakano, Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. E-mail address: hnakano{at}med.juntendo.ac.jp

³ Abbreviations used in this paper: LT, lymphotoxin; TNFR1, TNFR type 1; TRAF, TNFR-associated factor; PP, Peyer’s patch; MEF, murine embryonic fibroblast; LN, lymph node; MLN, mesenteric LN; ChIP, chromatin immunoprecipitation; WT, wild type.