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Copyright ©2012 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Orthop. Sep 18, 2012; 3(9): 142-150
Published online Sep 18, 2012. doi: 10.5312/wjo.v3.i9.142
RANKL-RANK interaction in immune regulatory systems
Taishin Akiyama, Miho Shinzawa, Nobuko Akiyama
Taishin Akiyama, Miho Shinzawa, Nobuko Akiyama, Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
Author contributions: Akiyama T, Shinzawa M and Akiyama N wrote parts of the manuscript, drew the figures and provided some intellectual comments; Akiyama T designed and edited the manuscript.
Correspondence to: Taishin Akiyama, Associate Professor, Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.
Telephone: +81-3-54495276 Fax: +81-3-54495421
Received: May 31, 2012
Revised: August 21, 2012
Accepted: September 15, 2012
Published online: September 18, 2012

The interaction between the receptor activator of NF-κB ligand (RANKL) and its receptor RANK plays a critical role in the development and function of diverse tissues. This review summarizes the studies regarding the functions of RANKL signaling in immune regulatory systems. Previous in vitro and in vivo studies have indicated that the RANKL signal promotes the survival of dendritic cells (DCs), thereby activating the immune response. In addition, RANKL signaling to DCs in the body surface barriers controls self-tolerance and oral-tolerance through regulatory T cell functions. In addition to regulating DC functions, the RANKL and RANK interaction is critical for the development and organization of several lymphoid organs. The RANKL signal initiates the formation of clusters of lymphoid tissue inducer cells, which is crucial for lymph node organogenesis. Moreover, the RANKL-RANK interaction controls the differentiation of M cells, specialized epithelial cells in mucosal tissues, that take up and transcytose antigen particles to control the immune response to pathogens or commensal bacterium. The development of epithelial cells localized in the thymic medulla (mTECs) is also regulated by the RANKL-RANK signal. Given that the unique property of mTECs to express a wide variety of tissue-specific self-antigens is critical for the elimination of self-antigen reactive T cells in the thymus, the RANKL-RANK interaction contributes to the suppression of autoimmunity. Future studies on the roles of the RANKL-RANK system in immune regulatory functions would be informative for the development and application of inhibitors of RANKL signaling for disease treatment.

Keywords: RANKL, T cells, Dendritic cells, Thymus, Medullary thymic epithelial cells, Lymphoid tissue inducer cells, Lymph node, M cells, Peyer’s patches