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View metadata, citation and similar papers at core.ac.uk brought to you by CORE MINI REVIEW ARTICLE published: 03 Septemberprovided by 2012 Frontiers - Publisher Connector doi: 10.3389/fimmu.2012.00261 Emerging functions of RANKL in lymphoid tissues

Christopher G. Mueller 1* and Estelle Hess 1,2

1 CNRS, Laboratory of Therapeutic Immunology and Chemistry, Institut de Biologie Moléculaire et Cellulaire, University of Strasbourg, Strasbourg, France 2 Unité de Recherche en Biologie Moléculaire, Facultés Universitaires Notre-Dame de la Paix Namur, Namur, Belgium

Edited by: The superfamily (TNFSF) members play pivotal roles in embryonic Burkhard Ludewig, Kantonal Hospital development of lymphoid tissue and their homeostasis. RANKL (Receptor activator of NF- St. Gallen, Switzerland κB ligand, also called TRANCE, TNFSF11) is recognized as an important player in bone Reviewed by: Annette Oxenius, Federal Institute of homeostasis and lymphoid tissue formation. In its absence bone mass control is deregu- Technology Zurich, Switzerland lated and lymph nodes fail to develop. While its function in bone is well described, there is Jorge Caamano, University of still little functional insight into the action of RANKL in lymphoid tissue development and Birmingham, UK homeostasis. Here we provide an overview of the known functions of RANKL, its signal- Ifor Williams, Emory University, USA ing receptor RANK and its decoy receptor OPG from the perspective of lymphoid tissue *Correspondence: Christopher G. Mueller, CNRS, development and immune activation in the mouse. Expressed by the hematopoietic lym- Laboratory of Therapeutic phoid tissue inducing (LTi) cells and the mesenchymal lymphoid tissue organizer (LTo) cells, Immunology and Chemistry, RANKL was shown to stimulate (LT) expression and to be implicated in LTi UPR9021, Institut de Biologie cell accumulation. Our recent finding that RANKL also triggers proliferation of adult lymph Moléculaire et Cellulaire, 15 Rue René Descartes, University of Strasbourg, node stroma suggests that RANKL may furthermore directly activate LTo cells. Beyond 67084 Strasbourg, France. bone, the RANKL-RANK-OPGtriad plays important roles in immunobiology that are waiting e-mail: [email protected] to be unraveled.

Keywords:TRANCE,TNFSF11, OPG, lymphoid organs, lymph node, stroma, LTi, LTo

INTRODUCTION The discovery of RANK, RANKL, and OPG in bone and the Tumor necrosis factor (TNF) and Lymphotoxin (LT) were iden- immune system raises the question of its evolutionary origins. The tified as the first members of a large family, now called the TNF- arose simultaneously during ontogeny of bony fish as evi- superfamily (SF). Not surprisingly, the receptors for these denced by sequence identification and presence of resorption also constitute a SF with , named TNF Recep- and remodeling activity of vertebrate mineralized tissue (Witten tor (TNFR) SF. A hallmark of these ligand-receptor pairs lies in a and Huysseune, 2009). They therefore postdate the formation of threefold symmetry,where by the oligomeric binding arrangement the primordial immune system comprising a primitive thymus and amplifies their avidity and introduces flexibility. Further complex- lymphoid structures associated with exposed sites. However, they ity arises through different partner affinities and generation of preceded the development of lymph nodes (LNs) and germinal soluble ligand and receptor forms (Bodmer et al., 2002). RANKL centers arising in amphibians and the emergence of LT β receptor, (TNFSF11) is the ligand of two receptors, RANK (TNFRSF11a) a key molecule in lymphoid development (Glenney and Wiens, and OPG (TNFRSF11b). OPG (osteoprotegerin) was the first of 2007; see below). It is therefore likely that the RANK-RANKL- this triad to be discovered (Simonet et al., 1997) in a search OPG protein triad was co-opted by the advanced immune system for an inhibitor of osteoclastogenesis (Tsuda et al., 1997). OPG- for higher order structure together with an efficient regulation of ligand was then isolated and cloned using OPG as bait (Lacey et al., immune cell output from the bone marrow before genesis of LT β 1998; Yasuda et al., 1998). OPG-ligand turned out to be identical receptor-regulated lymphoid tissues. to TRANCE (TNF-related activation induced ), cloned RANKL is a type-II transmembrane protein but can also exist during a search for apoptosis-regulatory genes in T cells (Wong in a soluble form by ectodomain shedding and alternative splicing et al., 1997b), and RANKL (Receptor activator of NF-κB) iden- (Ikeda et al., 2001; Hikita et al., 2006; Baud’huin et al., 2007). OPG tified as the ligand for RANK that had attracted attention for its comprises two C-terminal regions homologous to death domains homology to CD40 (Anderson et al., 1997). The affinity of RANKL of TNFR1 or TRAIL receptor, which were found to be func- for OPG is 1000-fold higher than for RANK (Nakagawa et al., tional when OPG was expressed with a transmembrane sequence 1998), which is dependent on the ability of OPG to homodimerize (Yamaguchi et al., 1998). Natural OPG is unlikely to transmit (Schneeweis et al., 2005). OPG is also a ligand for TNF-related signals because it misses the transmembrane sequence and is apoptosis-inducing ligand (TRAIL; Emery et al., 1998), however, secreted (Simonet et al., 1997). RANK comprises a transmem- its affinity for TRAIL is 10,000 times less compared to RANKL brane region and a large cytoplasmic domain. Upon interaction (Body et al., 2006) questioning the in vivo relevance of OPG- with the RANKL trimer RANK undergoes homotrimerization and TRAIL interaction. There is now an emerging consensus to refer activates recruitment of TNFR-associated factors (TRAFs; Galib- to the receptor as RANK and, as a consequence and for simplicity, ert et al., 1998; Wada et al., 2006). RANK binds five of the six its ligand is called RANKL. The acronym OPG has remained in use. known TRAF-proteins but TRAF6 seems particularly important

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for RANK signaling, because TRAF6−/− mice present similar phe- regulatory action (Roberts et al., 2012). In fact RANK signaling is notypes as Rank−/− mice (Naito et al., 1999). RANK signaling cas- a key event in the early stages of medullary thymic epithelial cell cades were mostly deciphered in the myeloid lineage and include (mTEC) formation, and its cooperation with LT and CD40 signals the canonical and the non-canonical NF-κB pathways (Raju et al., is required to establish a fully developed medullary microenvi- 2011). In mammary glands RANK-activation intersects with pro- ronment (Rossi et al., 2007; Akiyama et al., 2008; Hikosaka et al., liferative cues through cyclin D1, Id2, and Id4 (Schramek et al., 2008; Mouri et al., 2011). mTEC play a crucial role in self-tolerance 2011). RANK was recently found to play a role in mammary and by eliminating self-reactive αβT cells and by regulating the early in hair follicle epithelial stem cell activation (Schramek et al., 2010; production of γδT cells. Thymic CD3−CD4+ lymphoid tissue Duheron et al., 2011) and to induce intestinal microfold cells (M inducing (LTi) cells and Vγ5+ thymocytes as well as later aris- cells) differentiation via the Ets transcription factor Spi-B (Kanaya ing CD4+CD8− single positive thymocytes and γδT cells are et al., 2012). equipped with RANKL (Rossi et al., 2007; Hikosaka et al., 2008; Roberts et al., 2012). RANK and OPG are expressed by mTECs RANKL IN BONE AND HEMATOPOIESIS (Hikosaka et al., 2008). Animals defective in RANK signaling A number of reviews have been published on the role of these pro- also display abnormal hematopoiesis and hypogammaglob- teins in regulating bone mass (Suda et al., 1999; Walsh and Choi, ulinemia (Dougall et al., 1999; Kong et al., 1999). Although B 2003; Baud’huin et al., 2007; Leibbrandt and Penninger, 2010). cells express RANK, in particular in response to activation (Yun Rankl−/− and Rank−/− mice present osteopetrosis and lack of et al., 1998; Perlot and Penninger, 2012), a B cell-specific RANK teeth (Dougall et al., 1999; Kong et al., 1999), whereas Opg −/− knock-out mouse does not reproduce this phenotype (Perlot and animals exhibit osteoporosis (Bucay et al., 1998; Mizuno et al., Penninger, 2012), suggesting that the defect lies in bone marrow 1998; Yun et al., 2001). RANK activates the differentiation of bone or splenic stroma. matrix degrading osteoclasts (OCL) from myeloid precursor cells (Yasuda et al., 1998; Hsu et al., 1999; Figure 1). RANKL and OPG RANKL IN EARLY STAGES OF SECONDARY LYMPHOID are synthesized by the bone mesenchymal lineage and are under ORGAN DEVELOPMENT inflammatory and hormonal control (Udagawa et al.,1999; Takeda RANK and RANKL-deficient animals display a complete absence et al., 2003; Nakashima et al., 2011; Xiong et al., 2011). Another of LNs, defects in Peyer’s patches (PPs) and cryptopatches (CPs) source of RANKL is activated T cells that can cause abnormal and abnormalities of the spleen (Dougall et al., 1999; Kong et al., bone resorption by triggering osteoclastogenesis (Takayanagi et al., 1999; Kim et al., 2000; Knoop et al., 2011; Perlot and Penninger, 2000; Sato et al., 2006). 2012). Therefore the RANK-RANKL-OPG axis shares with the lymphopoiesis itself underlies RANK regulation LT and TNFα pathways the control of molecular and cellular as Rank−/− mice present a block in the progression to processes determinant in secondary lymphoid organ (SLO) devel- CD4−CD8−CD44−CD25− thymocytes (Kong et al., 1999). opment (Tumanov et al., 2003; Fritz and Gommerman, 2010). Recently it was shown that also Vγ5+ T cells are under RANK SLO formation is initiated around embryonic day (E) 15 with the recruitment of the hematopoietic LTi cells to a rudimentary organ anlage composed of mesenchymal and endothelial stroma (White et al., 2007; Vondenhoff et al., 2009; Benezech et al., 2011). The recruitment process is dependent on the CXCL13 produced by precursors of lymphoid tissue organizer (LTo) cells stimulated by neuronal production of retinoic acid (van de Pavert et al., 2009). This step is followed by a cross-talk between LTi cells that express RANK, RANKL, and LT, and LTo precursors that carry the LT receptor LTβR. LTβR engagement induces LTo cells to express RANKL and to attract larger numbers of LTi cells that upon clustering with LTo cells initiate LN orga- nization (Cupedo and Mebius, 2005; Koning and Mebius, 2011; Figure 2). In view of the finding that LTi cell recruitment is LT indepen- dent (Eberl et al., 2004; White et al., 2007; Vondenhoff et al., 2009) the question arises whether LTi cell accumulation is regulated by RANK. Both Rankl−/− and Ltα−/− mice have lower number of LTi cells in mesenteric LNs of newborn mice (Kim et al., 2000). FIGURE 1 | RANKL function in the bone, the −/− and the vascular system. (A) RANKL produced by bone marrow stroma TRAF6 mice display fewer LTi cells in mesenteric LNs at E 17.5 (osteoblasts and osteocytes) directs the differentiation of preosteoclasts of but not at E15.5 (Yoshida et al., 2002). Administration of RANK- the myeloid lineage into mature osteoclasts. Stroma-derived OPG Fc antagonist led to a partial reduction in LTi cells, with a more negatively regulates RANKL-RANK interaction. (B) Activated T cells express prominent effect in mesenteric LNs (Eberl et al., 2004). Therefore, RANKL that stimulates survival and maturation. (C) although current data do not unambiguously support RANKL as Endothelium is a source for RANKL and OPG. RANK-activation of endothelial cells supports cell survival and promotes angiogenesis. a direct regulator of LTi cell numbers, they sustain the concept that RANKL is instrumental for LTi cell accumulation. Of note,

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RANKL AND SLO GROWTH A number of observations support a role of RANKL in SLO growth. The LNs that developed after neutralization of RANK signaling in embryos were smaller (Eberl et al., 2004; Sugiyama et al., 2012). PPs, CPs, and isolated lymphoid follicles (ILFs) were reduced in size in Rankl−/− mice (Knoop et al., 2011), and post- natal RANKL overproduction led to massive LN hyperplasia (Hess et al., 2012). Recruitment of immune cells and divi- sion stand out among possible regulatory mechanisms of SLO size. recruitment into SLO anlage coincides with matura- tion of LTo cells to produce high levels of chemokines and cell adhesion molecules (Honda et al., 2001; Finke et al., 2002; Luther FIGURE 2 | RANKL-dependent amplification loops in SLO development. et al., 2003; Cupedo et al., 2004b; White et al., 2007; Benezech et al., SLO development during embryogenesis is initiated by the recruitment of 2011). In mice with postnatal LN hyperplasia RANKL upregulates lymphoid tissue inducer (LTi) cells to a rudimentary organ anlage composed of mesenchymal lymphoid tissue organizer (LTo) cell progenitors. This step CXCL13, CCL19, MAdCAM-1, and VCAM-1 gene transcription is followed by a cross-talk between LTi cells that express RANKL, RANK, in adult fibroblastic reticular cells (FRCs) and vascular cells (Hess and LTαβ and LTo cells that carry LTβR . Engagement of the latter induces et al., 2012). Therefore, RANKL could directly boost immune cell the maturation of LTo cells to express RANKL and chemokines that accumulation by increased chemokine and adhesion factor output. attract larger numbers of LTi cells that upon clustering with LTo cells initiate LN organization. LTo cells also express RANKL. The current model of LN While recruitment of stromal precursors from surrounding tissue development indicates that a positive feedback loop takes place between or bone cannot be excluded, CD45-negative cells label for the cell LTo and LTi cells via RANKL-RANK and LTαβ-LTβR amplifying the early division marker Ki-67 as early as E16 (Eberl et al., 2004; White stages of LN development . If LTo cells expressed also RANK, a second et al., 2007). Although this proliferation appears to be dependent (autocrine) loop may occur, leading to a direct activation of LTo cells . on LT (White et al., 2007), it is unclear whether the proliferat- ing cells are endothelial cells, precursor or mature LTo cells. We have found that RANKL stimulates FRC and endothelial cell pro- RANK signaling mediators include Id2 (Kim et al., 2011), a fac- liferation (Hess et al., 2012). Further support for a functionally tor indispensable for LTi cell formation (Yokota et al., 1999). It is important role of RANKL in cell proliferation stems from findings hence plausible that Id2 is implicated in RANK regulation of LTi that thymic mTECs and skin keratinocyte cell growth is accelerated cell numbers and function. in response to RANK stimulation (Hikosaka et al., 2008; Duheron In the current model of LN development a positive feedback et al., 2011). loop takes place between LTi and LTo cells (Figure 2). RANK signaling in LTi cells increases the expression of LT that upon TOWARD A ROLE OF RANKL IN B CELL RECRUITMENT AND binding to LTβR of LTo cells induces RANKL production, thus FOLLICLE ORGANIZATION amplifying the early stages of LN development (Yoshida et al., B cell recruitment and organization into follicles occur in a 2002; Koning and Mebius, 2011; Roozendaal and Mebius, 2011). CXCL13-dependent manner at later stages of SLO formation In support for such a feedback loop is the observation that RANKL (Ansel et al., 2000; Cupedo et al., 2004a). B cell follicular den- expression is up to 10-fold higher in LTo cells than in LTi cells dritic cells (FDCs) and the recently identified marginal reticular (Sugiyama et al., 2012). However, it is unlikely that the function cells (MRCs), both mesenchymal cell types, are the main produc- of RANKL in SLO development is limited to the induction of LT ers of this chemokine (Ansel et al., 2000; Katakai et al., 2008). First by LTi cells and the creation of the amplification loop. Firstly, LT supportive evidence for a role of RANKL in B cell recruitment and is upregulated by a number of other factors, such as IL-7, TNFα, organization was provided after the rescue of LNs by exogenous and CXCL13 (Ansel et al., 2002). Indeed PPs are LT-dependent IL-7 in TRAF6−/− mice: it was noted that in these LNs B cells and but develop in Rankl−/− mice. Second, mucosal LNs develop in FDCs were absent (Yoshida et al., 2002). However, because TRAF6 LTβ−/− mice but not in Rankl−/− mice (Alimzhanov et al., 1997; is also a signaling component for TNFR, a critical receptor for Koni et al., 1997). Finally, administration of an LTβR-agonistic FDC formation (Rennert et al., 1998; Endres et al., 1999), a role of antibody to Rankl−/− embryos cannot rescue LN genesis (Kim RANK signaling in B cell recruitment cannot be directly invoked. et al., 2000). More direct evidence was provided by administration of a RANKL- LTβR signaling in mTECs induces RANK expression (Mouri neutralizing antibody to embryos. This resulted in reduced LN B et al., 2011). We have recently shown that RANK is expressed cells numbers, misplaced FDCs, and reduced VCAM-1 staining in adult LN stroma and induces hyperproliferation of reticular (Sugiyama et al., 2012). In addition, Knoop et al.(2011) noted an fibroblastic and vascular cells (Hess et al., 2012). Expression of absence of B cells in small intestine CPs of Rankl −/− mice and both RANK and RANKL by LTo cells may therefore trigger a observed that most stromal cells in the B cell compartment lacked second (autocrine) loop leading to a direct activation of these VCAM-1 and CXCL13 expression. Finally, postnatal RANKL over- cells (Figure 2). In addition, vascular endothelial cells express expression resulted in an increase in small but clearly defined RANK, RANKL, and OPG that together regulate angiogenesis B cell follicles, which all comprised FDCs (Hess et al., 2012). (Kim et al., 2003; Benslimane-Ahmim et al., 2011; Sugiyama et al., Three possible scenarios can be advanced to explain these phe- 2012; Figure 1). nomena: (i) RANKL increases the bone marrow B cell output, (ii)

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CXCL13 production by FDCs and/or MRCs is under RANKL pos- may be due to low RANK expression level in immature DCs; itive control, (iii) RANK-signaling promotes MRC and/or FDC its expression being upregulated in response to Toll-like recep- differentiation. Although the first scenario appears plausible in tor (TLR) ligands or inflammatory (Hochweller and view of the known action of RANKL in the bone, so far, there is Anderton,2005). Another explanation could be a redundancy with no experimental support for this idea. The rise in LN B cell num- other TNFRSF members such as its close homolog CD40 (Bach- bers in response to RANKL overproduction is not accompanied mann et al., 1999). Alternatively, activated DCs express OPG, thus by an expansion in splenic transitional B cell subsets (Hess et al., inhibiting RANKL (Schoppet et al., 2007). Except for a reduction 2012). As for the second model, there is evidence that RANKL in Langerhans cell numbers (Barbaroux et al., 2008), there is little upregulates CXCL13 gene transcription in FRCs, however the experimental support that the RANK-RANKL-OPG triad controls level of induction was low (Hess et al., 2012). Lastly, reduction DC development in vivo (Dougall et al., 1999). of VCAM-1 expression by FDCs is indicative of a requirement of Th17 T cells represent an important osteoclastogenic T cell type RANK-signaling for terminal differentiation of FDCs. In keep- by robust RANKL production and activation of RANKL release by ing with this idea, reduced CXCL13 expression by FDCs could be mesenchymal cells (Sato et al., 2006). This T cell type is of par- the consequence of FDC dysfunction. It is intriguing that MRCs, ticular importance in progressive periodontitis, a dental disease which have been proposed to function as FDC precursors, express characterized by destruction of alveolar bone with high prevalence RANKL (Katakai et al., 2008). Cells that bear resemblance to LN of bacteria such as Porphyromonas gingivalis (Kajiya et al., 2010). MRCs have also been found in the spleen, PP, and ILF on the In this disease, periodontal ligament fibroblasts are an important grounds of RANKL expression and independence of LTβR sig- source of RANKL when stimulated by microbial products includ- naling (Taylor et al., 2007; Katakai et al., 2008). The polarized ing TLR ligands. TLRs are also expressed by osteoclast precursors expression of RANKL beneath the follicle-associated and OCL and their stimulation promotes osteoclastogenesis and may be necessary to focus its activity of inducing differentiation maturation of OCL. Interestingly, gingival Langerin-expressing of intestinal M cells, cells specialized in the transport of antigen to DCs have recently been shown to control inflammation in P. gin- the underlying lymphoid tissue (Knoop et al., 2009). It is plausi- givalis-induced periodontitis and therefore reduce alveolar bone ble that RANKL jointly regulates FDC differentiation and (native) loss (Arizon et al., 2012). It is yet unclear whether this occurs via a antigen access. direct RANKL-induced DC anti-inflammatory activity.

RANKL AND THE ADAPTIVE IMMUNE RESPONSE CONCLUSION Activated CD4 and CD8 T cells express surface and soluble RANKL The RANK-RANKL-OPG axis plays a recognized role in bone (Josien et al., 1999; Wang et al., 2002; Figure 1). Dendritic cells homeostasis through the regulation of osteoclastogenesis. It is also are of the same lineage as OCL and express RANK (Anderson implicated in SLO development and regulation of the immune et al., 1997). RANKL confers to DCs better survival with more response. There are many incentives to answer remaining ques- notable effects on in vitro generated DCs and in combination tions. In addition to a restless curiosity of the researcher, tertiary with other TNFSF members (Wong et al., 1997a; Dougall et al., lymphoid tissues that arise in inflamed tissue rely on similar if 1999; Josien et al., 2000; Williamson et al., 2002). Stimulation not identical cellular dialogs as those found in SLO development. of DCs results in production of pro-inflammatory cytokines IL- Defining RANKL function in lymphoid tissue development will 6, IL-1β, and T cell differentiation factors IL-12, IL-15 (Josien open new therapeutic avenues to treat inflammatory diseases and et al., 1999). However, other reports have noted anti-inflammatory provide new strategies for vaccine development. activity for RANKL. In a model of oral tolerance, RANKL stim- ulation of DCs has been associated with tolerance induction ACKNOWLEDGMENTS (Williamson et al., 2002). An anti-inflammatory effect was also This work was supported by CNRS, University of Strasbourg, La noted for RANKL-stimulated Langerhans cells and Ligue contre le Cancer (to Estelle Hess) and the Fondation de (Maruyama et al., 2006; Yoshiki et al., 2009). This discrepancy Recherche Médicale.

REFERENCES Abnormal development of antibody production, and body Natl. Acad. Sci. U. S. A. 109, Akiyama, T., Shimo, Y., Yanai, H., secondary lymphoid tissues in cavity immunity. Immunity 16, 7043–7048. Qin, J., Ohshima, D., Maruyama, Y., -deficient mice. 67–76. Bachmann, M. F., Wong, B. R., Asaumi, Y., Kitazawa, J., Takayanagi, Proc. Natl. Acad. Sci. U.S.A. 94, Ansel, K. M., Ngo, V. N., Hyman, P. L., Josien, R., Steinman, R. M., Oxe- H., Penninger, J. M., Matsumoto, 9302–9307. Luther, S. A., Forster, R., Sedgwick, nius, A., and Choi, Y. (1999). M., Nitta, T., Takahama, Y., and Anderson, D. M., Maraskovsky, E., J. D., Browning, J. L., Lipp, M., and TRANCE, a tumor necrosis fac- Inoue, J. (2008). The tumor necro- Billingsley, W. L., Dougall, W. C., Cyster, J. G. (2000). A chemokine- tor family member critical for sis factor family receptors RANK Tometsko, M. E., Roux, E. R., Teepe, driven positive feedback loop orga- CD40 ligand-independent T helper and CD40 cooperatively establish M. C., DuBose, R. F., Cosman, D., nizes lymphoid follicles. Nature 406, cell activation. J. Exp. Med. 189, the thymic medullary microenvi- and Galibert, L. (1997). A homo- 309–314. 1025–1031. ronment and self-tolerance. Immu- logue of the TNF receptor and its Arizon, M., Nudel, I., Segev, H., Barbaroux, J. B., Beleut, M., Brisken, nity 29, 423–437. ligand enhance T-cell growth and Mizraji, G., Elnekave, M., Furmanov, C., Mueller, C. G., and Groves, Alimzhanov, M. B., Kuprash, D. V., dendritic-cell function. Nature 390, K., Eli-Berchoer, L., Clausen, B. R. (2008). Epidermal receptor Kosco-Vilbois, M. H., Luz, A., 175–179. E., Shapira, L., Wilensky, A., and activator of NF-kB ligand con- Turetskaya, R. L., Tarakhovsky, Ansel, K. M., Harris, R. B., and Hovav, A. H. (2012). Langerhans trols langerhans cell numbers and A., Rajewsky, K., Nedospasov, Cyster, J. G. (2002). CXCL13 is cells down-regulate inflammation- proliferation. J. Immunol. 181, S. A., and Pfeffer, K. (1997). required for B1 cell homing, natural driven alveolar bone loss. Proc. 1103–1108.

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Baud’huin, M., Lamoureux, F., Dougall, W. C., Glaccum, M., Char- Glenney, G. W., and Wiens, G. D. factor-kappaB ligand and their dif- Duplomb, L., Redini, F., and rier, K., Rohrbach, K., Brasel, K., (2007). Early diversification of ferential expression in bone and thy- Heymann, D. (2007). RANKL, De Smedt, T., Daro, E., Smith, the TNF superfamily in teleosts: mus. Endocrinology 142, 1419–1426. RANK, osteoprotegerin: key part- J., Tometsko, M. E., Maliszewski, genomic characterization and Josien, R., Li, H. L., Ingulli, E., Sarma, ners of osteoimmunology and C. R., Armstrong, A., Shen, V., expression analysis. J. Immunol. 178, S., Wong, B. R., Vologodskaia, M., vascular diseases. Cell. Mol. Life Sci. Bain, S., Cosman, D., Anderson, 7955–7973. Steinman,R. M.,and Choi,Y.(2000). 64, 2334–2350. D., Morrissey, P. J., Peschon, J. J., Hess, E., Duheron, V., Decossas, M., TRANCE, a tumor necrosis fac- Benezech, C., White, A., Mader, E., and Schuh, J. (1999). RANK is Lézot, F., Berdal, A., Chea, S., Golub, tor family member, enhances the Serre, K., Parnell, S., Pfeffer, K., essential for osteoclast and lymph R., Bosisio, M. R., Bridal, S. L., longevity and adjuvant properties of Ware, C. F., Anderson, G., and Caa- node development. Genes Dev. 13, Choi, Y., Yagita, H., and Mueller, C. dendritic cells in vivo. J. Exp. Med. mano, J. H. (2011). Ontogeny of 2412–2424. G. (2012). RANKL induces orga- 191, 495–502. stromal organizer cells during lymph Duheron,V.,Hess, E., Duval, M., Decos- nized lymph node growth by stromal Josien, R., Wong, B. R., Li, H. L., Stein- node development. J. Immunol. 184, sas, M., Castaneda, B., Klöpper, J. cell proliferation. J. Immunol. 188, man, R. M., and Choi, Y. (1999). 4521–4530. E., Amoasii, L., Barbaroux, J. B., 1245–1254. TRANCE, a TNF family mem- Benslimane-Ahmim, Z., Heymann, D., Williams, I. R., Yagita, H., Penninger, Hikita,A.,Yana,I.,Wakeyama,H.,Naka- ber, is differentially expressed on T Dizier, B., Lokajczyk, A., Brion, R., J. M., Choi, Y., Lezot, F., Groves, mura, M., Kadono, Y., Oshima, Y., cell subsets and induces cytokine Laurendeau, I., Bieche, I., Smadja, R., Paus, R., and Mueller, C. G. Nakamura, K., Seiki, M., and Tanaka, production in dendritic cells. J. D. M., Galy-Fauroux, I., Colliec- (2011). Receptor Activator of NF-kB S. (2006). Negative regulation of Immunol. 162, 2562–2568. Jouault, S., Fischer, A. M., and (RANK) stimulates the proliferation osteoclastogenesis by ectodomain Kajiya, M., Giro, G., Taubman, M. Boisson-Vidal, C. (2011). Osteopro- of epithelial cells of the epidermo- shedding of receptor activator of A., Han, X., Mayer, M. P., and tegerin, a new actor in vasculogen- pilosebaceous unit. Proc. Natl. Acad. NF-kappaB ligand. J. Biol. Chem. Kawai, T. (2010). Role of periodon- esis, stimulates endothelial colony- Sci. U.S.A. 108, 5342–5347. 281, 36846–36855. tal pathogenic bacteria in RANKL- forming cells properties. J. Thromb. Eberl, G., Marmon, S., Sunshine, M. Hikosaka, Y., Nitta, T., Ohigashi, I., mediated bone destruction in peri- Haemost. 9, 834–843. J., Rennert, P. D., Choi, Y., and Yano, K., Ishimaru, N., Hayashi, Y., odontal disease. J. Oral Microbiol. 2, Bodmer, J. L., Schneider, P., and Littman, D. R. (2004). An essen- Matsumoto, M., Matsuo, K., Pen- 5532–5548. Tschopp, J. (2002). The molecular tial function for the nuclear receptor ninger, J. M., Takayanagi, H., Yokota, Kanaya, T., Hase, K., Takahashi, D., architecture of the TNF superfamily. RORgamma(t) in the generation of Y., Yamada, H., Yoshikai, Y., Inoue, Fukuda, S., Hoshino, K., Sasaki, I., Trends Biochem. Sci. 27, 19–26. fetal lymphoid tissue inducer cells. J., Akiyama, T., and Takahama, Hemmi,H.,Knoop,K.A.,Kumar,N., Body, J. J., Facon, T., Coleman, R. Nat. Immunol. 5, 64–73. Y. (2008). The cytokine RANKL Sato, M., Katsuno, T., Yokosuka, O., E., Lipton, A., Geurs, F., Fan, M., Emery, J. G., McDonnell, P., Burke, M. produced by positively selected Toyooka,K.,Nakai,K.,Sakamoto,A., Holloway, D., Peterson, M. C., B., Deen, K. C., Lyn, S., Silverman, thymocytes fosters medullary Kitahara, Y., Jinnohara, T., McSor- and Bekker, P. J. (2006). A study C., Dul, E., Appelbaum, E. R., Eich- thymic epithelial cells that express ley, S. J., Kaisho, T., Williams, I. R., of the biological receptor activa- man, C., DiPrinzio, R., Dodds, R. A., autoimmune regulator. Immunity and Ohno, H. (2012). The Ets tran- tor of nuclear factor-kappaB ligand James, I. E., Rosenberg, M., Lee, J. C., 29, 438–450. scription factor Spi-B is essential inhibitor, , in patients and Young, P.R. (1998). Osteoprote- Hochweller, K., and Anderton, S. M. for the differentiation of intestinal with or bone gerin is a receptor for the cytotoxic (2005). Kinetics of costimulatory microfold cells. Nat. Immunol. 13, metastases from breast cancer. Clin. ligand TRAIL. J. Biol. Chem. 273, molecule expression by T cells and 729–736. Cancer Res. 12, 1221–1228. 14363–14367. dendritic cells during the induc- Katakai, T., Suto, H., Sugai, M., Bucay, N., Sarosi, I., Dunstan, C. R., Endres, R., Alimzhanov, M. B., Plitz, T., tion of tolerance versus immu- Gonda, H., Togawa, A., Suematsu, S., Morony,S.,Tarpley,J.,Capparelli,C., Futterer, A., Kosco-Vilbois, M. H., nity in vivo. Eur. J. Immunol. 35, Ebisuno, Y., Katagiri, K., Kinashi, T., Scully, S., Tan, H. L., Xu, W., Lacey, Nedospasov, S. A., Rajewsky, K., and 1086–1096. and Shimizu, A. (2008). Organizer- D. L., Boyle, W. J., and Simonet, W. Pfeffer, K. (1999). Mature follicu- Honda, K., Nakano, H., Yoshida, like reticular stromal cell layer com- S. (1998). osteoprotegerin-deficient lar dendritic cell networks depend H., Nishikawa, S., Rennert, P., mon to adult secondary lymphoid mice develop early onset osteoporo- on expression of lymphotoxin beta Ikuta, K., Tamechika, M., Yam- organs. J. Immunol. 181, 6189–6200. sis and arterial calcification. Genes receptor by radioresistant stromal aguchi, K., Fukumoto, T., Chiba, Kim, D., Mebius, R. E., MacMicking, Dev. 12, 1260–1268. cells and of lymphotoxin beta and T., and Nishikawa, S. I. (2001). J. D., Jung, S., Cupedo, T., Castel- Cupedo, T., Lund, F. E., Ngo, V. N., Ran- tumor necrosis factor by B cells. J. Molecular basis for hematopoi- lanos, Y., Rho, J., Wong, B. R., dall, T. D., Jansen, W., Greuter, M. J., Exp. Med. 189, 159–168. etic/mesenchymal interaction dur- Josien, R., Kim, N., Rennert, P. D., de Waal-Malefyt, R., Kraal, G., Cys- Finke, D., Acha-Orbea, H., Mattis, ing initiation of Peyer’s patch and Choi, Y. (2000). Regulation of ter, J. G., and Mebius, R. E. (2004a). A., Lipp, M., and Kraehenbuhl, J. organogenesis. J. Exp. Med. 193, peripheral lymph node genesis by Initiation of cellular organization (2002). CD4+CD3− cells induce 621–630. the tumor necrosis factor family in lymph nodes is regulated by Peyer’s patch development: role of Hsu, H., Lacey, D. L., Dunstan, C. R., member TRANCE. J. Exp. Med. 192, non-B cell-derived signals and is not alpha4beta1 integrin activation by Solovyev, I., Colombero, A., Timms, 1467–1478. dependent on CXC chemokine CXCR5. Immunity 17, 363–373. E., Tan,H. L., Elliott, G., Kelley, M. J., Kim, H. H., Shin, H. S., Kwak, H. J., ligand 13. J. Immunol. 173, Fritz, J. H., and Gommerman, J. L. Sarosi, I., Wang, L., Xia, X. Z., Elliott, Ahn, K. Y., Kim, J. H., Lee, H. J., 4889–4896. (2010). Cytokine/stromal cell net- R., Chiu, L., Black, T., Scully, S., Cap- Lee, M. S., Lee, Z. H., and Koh, G. Y. Cupedo, T., Vondenhoff, M. F., Heere- works and lymphoid tissue envi- parelli, C., Morony, S., Shimamoto, (2003). RANKL regulates endothe- grave, E. J., De Weerd, A. E., Jansen, ronments. J. Cytokine Res. G., Bass, M. B., and Boyle, W. J. lial cell survival through the phos- W., Jackson, D. G., Kraal, G., and 6. (1999). Tumor necrosis factor recep- phatidylinositol 30-kinase/Akt signal Mebius, R. E. (2004b). Presumptive Galibert, L., Tometsko, M. E., Anderson, tor family member RANK mediates transduction pathway. FASEB J. 17, lymph node organizers are differ- D. M., Cosman, D., and Dougall, W. osteoclast differentiation and activa- 2163–2165. entially represented in developing C. (1998). The involvement of mul- tion induced by osteoprotegerin lig- Kim, N. S., Kim, H. T., Kwon, M. C., mesenteric and peripheral nodes. J. tiple tumor necrosis factor recep- and. Proc. Natl. Acad. Sci. U.S.A. 96, Choi, S. W., Kim, Y. Y., Yoon, K. Immunol. 173, 2968–2975. tor (TNFR)-associated factors in the 3540–3545. J., Koo, B. K., Kong, M. P., Shin, Cupedo, T., and Mebius, R. E. (2005). signaling mechanisms of receptor Ikeda, T., Kasai, M., Utsuyama, M., J., Cho, Y., and Kong, Y. Y. (2011). Cellular interactions in lymph node activator of NF-kappaB, a member and Hirokawa, K. (2001). Deter- Survival and differentiation of mam- development. J. Immunol. 174, of the TNFR superfamily. J. Biol. mination of three isoforms of mary epithelial cells in mammary 21–25. Chem. 273, 34120–34127. the receptor activator of nuclear gland development require nuclear

www.frontiersin.org September 2012 | Volume 3 | Article 261| 5 Mueller and Hess RANKL-responses in the immune system

retention of Id2 due to RANK signal- proinflammatory cytokine produc- S. (1998). Lymph node genesis is and breast cancer metastasis. Trends ing. Mol. Cell. Biol. 31, 4775–4788. tion in mice. J. Immunol. 177, induced by signaling through the Endocrinol. Metab. 22, 188–194. Knoop, K. A., Butler, B. R., Kumar, N., 3799–3805. lymphotoxin beta receptor. Immu- Simonet, W. S., Lacey, D. L., Dunstan, C. Newberry, R. D., and Williams, I. Mizuno, A., Amizuka, N., Irie, K., nity 9, 71–79. R., Kelley, M., Chang, M. S., Luthy, R. (2011). Distinct developmental Murakami, A., Fujise, N., Kanno, T., Roberts, N. A., White, A. J., Jenkin- R., Nguyen, H. Q., Wooden, S., Ben- requirements for isolated lymphoid Sato, Y., Nakagawa, N., Yasuda, H., son, W. E., Turchinovich, G., Naka- nett, L., Boone, T., Shimamoto, G., follicle formation in the small and Mochizuki, S., Gomibuchi, T., Yano, mura, K., Withers, D. R., McConnell, DeRose, M., Elliott, R., Colombero, large intestine RANKL is essential K., Shima, N., Washida, N., Tsuda, F. M., Desanti, G. E., Benezech, C., A., Tan, H. L., Trail, G., Sullivan, J., only in the small intestine. Am. J. E., Morinaga, T., Higashio, K., and Parnell, S. M., Cunningham, A. F., Davy, E., Bucay, N., Renshaw-Gegg, Pathol. 179, 1861–1871. Ozawa, H. (1998). Severe osteoporo- Paolino, M., Penninger, J. M., Simon, L., Hughes, T. M., Hill, D., Pattison, Knoop, K. A., Kumar, N., Butler, B. R., sis in mice lacking osteoclastogenesis A. K., Nitta, T., Ohigashi, I., Taka- W., Campbell, P., Sander, S., Van, G., Sakthivel, S. K., Taylor, R. T., Nochi, inhibitory factor/osteoprotegerin. hama, Y., Caamano, J. H., Hayday, A. Tarpley, J., Derby, P., Lee, R., and T., Akiba, H., Yagita, H., Kiyono, H., Biochem. Biophys. Res. Commun. C., Lane, P. J., Jenkinson, E. J., and Boyle, W. J. (1997). Osteoprotegerin: and Williams, I. R. (2009). RANKL 247, 610–615. Anderson, G. (2012). Rank signal- a novel secreted protein involved in is necessary and sufficient to initiate Mouri, Y., Yano, M., Shinzawa, M., ing links the development of invari- the regulation of bone density. Cell development of antigen-sampling M Shimo, Y., Hirota, F., Nishikawa, ant gammadelta T cell progenitors 89, 309–319. cells in the intestinal epithelium. J. Y., Nii, T., Kiyonari, H., Abe, T., and aire(+) medullary epithelium. Suda, T., Takahashi, N., Udagawa, N., Immunol. 183, 5738–5747. Uehara, H., Izumi, K., Tamada, Immunity 36, 427–437. Jimi, E., Gillespie, M. T., and Martin, Kong, Y. Y., Yoshida, H., Sarosi, I., Tan, K., Chen, L., Penninger, J. M., Roozendaal, R., and Mebius, R. E. T.J. (1999). Modulation of osteoclast H. L., Timms, E., Capparelli, C., Inoue, J. I., Akiyama, T., and Mat- (2011). Stromal cell-immune cell differentiation and function by the Morony, S., Oliveira-dos-Santos, A. sumoto, M. (2011). Lymphotoxin interactions. Annu. Rev. Immunol. new members of the tumor necrosis J., Van, G., Itie, A., Khoo, W., Wake- signal promotes thymic organogen- 29, 23–43. factor receptor and ligand families. ham, A., Dunstan, C. R., Lacey, D. esis by eliciting RANK expression Rossi, S. W., Kim, M. Y., Leibbrandt, Endocr. Rev. 20, 345–357. L., Mak, T. W., Boyle, W. J., and in the embryonic thymic stroma. J. A., Parnell, S. M., Jenkinson, W. Sugiyama, M., Nakato, G., Jinnohara, Penninger, J. M. (1999). OPGL is Immunol. 186, 5047–5057. E., Glanville, S. H., McConnell, T., Akiba, H., Okumura, K., Ohno, a key regulator of osteoclastogen- Naito, A., Azuma, S., Tanaka, S., F. M., Scott, H. S., Penninger, J. H., and Yoshida, H. (2012). Expres- esis, lymphocyte development and Miyazaki, T., Takaki, S., Takatsu, M., Jenkinson, E. J., Lane, P. J., sion pattern changes and function of lymph-node organogenesis. Nature K., Nakao, K., Nakamura, K., and Anderson, G. (2007). RANK RANKL during mouse lymph node 397, 315–323. Katsuki, M., Yamamoto, T., and signals from CD4 + 3- inducer microarchitecture development. Int. Koni, P. A., Sacca, R., Lawton, P., Inoue, J. (1999). Severe osteopetro- cells regulate development of Aire- Immunol. 2012, 21. Browning, J. L., Ruddle, N. H., and sis, defective -1 signalling expressing epithelial cells in the Takayanagi, H., Ogasawara, K., Hida, Flavell, R. A. (1997). Distinct roles and lymph node organogenesis in thymic medulla. J. Exp. Med. 14, 14. S., Chiba, T., Murata, S., Sato, in lymphoid organogenesis for lym- TRAF6-deficient mice. Genes Cells 4, Sato, K., Suematsu, A., Okamoto, K., Takaoka, A., Yokochi, T., Oda, photoxins alpha and beta revealed 353–362. K., Yamaguchi, A., Morishita, Y., H., Tanaka, K., Nakamura, K., in lymphotoxin beta-deficient mice. Nakagawa, N., Kinosaki, M.,Yamaguchi, Kadono, Y., Tanaka, S., Kodama, T., and Taniguchi, T. (2000). T-cell- Immunity 6, 491–500. K., Shima, N., Yasuda, H., Yano, Akira, S., Iwakura, Y., Cua, D. J., mediated regulation of osteoclas- Koning, J. J., and Mebius, R. E. (2011). K., Morinaga, T., and Higashio, K. and Takayanagi, H. (2006). Th17 togenesis by signalling cross-talk Interdependence of stromal and (1998). RANK is the essential sig- functions as an osteoclastogenic between RANKL and IFN-gamma. immune cells for lymph node func- naling receptor for osteoclast differ- helper T cell subset that links T cell Nature 408, 600–605. tion. Trends Immunol. 33, 264–270. entiation factor in osteoclastogene- activation and bone destruction. J. Takeda, S., Elefteriou, F., and Karsenty, Lacey, D. L., Timms, E., Tan, H. L., Kel- sis. Biochem. Biophys. Res. Commun. Exp. Med. 203, 2673–2682. G. (2003). Common endocrine con- ley, M. J., Dunstan, C. R., Burgess, 253, 395–400. Schneeweis, L. A.,Willard, D., and Milla, trol of body weight, reproduction, T., Elliott, R., Colombero, A., Elliott, Nakashima, T., Hayashi, M., Fukunaga, M. E. (2005). Functional dissection and bone mass. Annu. Rev. Nutr. 23, G., Scully, S., Hsu, H., Sullivan, J., T., Kurata, K., Oh-Hora, M., Feng, of osteoprotegerin and its interac- 403–411. Hawkins, N., Davy, E., Capparelli, J. Q., Bonewald, L. F., Kodama, tion with receptor activator of NF- Taylor, R. T., Patel, S. R., Lin, E., But- C., Eli, A., Qian, Y. X., Kaufman, S., T., Wutz, A., Wagner, E. F., Pen- kappaB ligand. J. Biol. Chem. 280, ler, B. R., Lake, J. G., Newberry, Sarosi, I., Shalhoub, V., Senaldi, G., ninger, J. M., and Takayanagi, H. 41155–41164. R. D., and Williams, I. R. (2007). Guo, J., Delaney, J., and Boyle, W. (2011). Evidence for osteocyte regu- Schoppet, M., Henser, S., Ruppert, V., Lymphotoxin-independent expres- J. (1998). Osteoprotegerin ligand is lation of bone homeostasis through Stubig, T., Al-Fakhri, N., Maisch, B., sion of TNF-related activation- a cytokine that regulates osteoclast RANKL expression. Nat. Med. 17, and Hofbauer, L. C. (2007). Osteo- induced cytokine by stromal cells differentiation and activation. Cell 1231–1234. protegerin expression in dendritic in cryptopatches, isolated lymphoid 93, 165–176. Perlot, T., and Penninger, J. M. cells increases with maturation and follicles, and Peyer’s patches. J. Leibbrandt, A., and Penninger, J. (2012). Development and function is NF-kappaB-dependent. J. Cell. Immunol. 178, 5659–5667. M. (2010). Novel Functions of of murine B cells lacking RANK. J. Biochem. 100, 1430–1439. Tsuda, E., Goto, M., Mochizuki, S.,Yano, RANK(L) Signaling in the Immune Immunol. 188, 1201–1205. Schramek, D., Leibbrandt, A., Sigl, V., K., Kobayashi, F., Morinaga, T., and System. Adv. Exp. Med. Biol. 658, Raju, R., Balakrishnan, L., Nanjappa, Kenner, L., Pospisilik, J. A., Lee, Higashio, K. (1997). Isolation of a 77–94. V., Bhattacharjee, M., Getnet, D., H. J., Hanada, R., Joshi, P. A., novel cytokine from human fibrob- Luther, S. A., Ansel, K. M., and Cys- Muthusamy, B., Kurian Thomas, J., Aliprantis, A., Glimcher, L., Pas- lasts that specifically inhibits osteo- ter, J. G. (2003). Overlapping roles Sharma, J., Rahiman, B. A., Har- parakis, M., Khokha, R., Ormandy, clastogenesis. Biochem. Biophys. Res. of CXCL13, receptor sha, H. C., Shankar, S., Prasad, T. C. J., Widschwendter, M., Schett, G., Commun. 234, 137–142. alpha, and CCR7 ligands in lymph S., Mohan, S. S., Bader, G. D., and Penninger, J. M. (2010). Osteo- Tumanov, A. V., Kuprash, D. V., and node development. J. Exp. Med. 197, Wani, M. R., and Pandey, A. (2011). clast differentiation factor RANKL Nedospasov, S. A. (2003). The role 1191–1198. A comprehensive manually curated controls development of progestin- of lymphotoxin in development and Maruyama,K.,Takada,Y.,Ray,N.,Kishi- reaction map of RANKL/RANK- driven mammary cancer. Nature maintenance of secondary lymphoid moto, Y., Penninger, J. M., Yasuda, signaling pathway. Database 2011. 468, 98–102. tissues. Cytokine Rev. H., and Matsuo, K. (2006). Recep- doi: 10.1093/database/bar021 Schramek, D., Sigl, V., and Penninger, 14, 275–288. tor activator of NF-kappa B lig- Rennert, P. D., James, D., MacKay, F., J. M. (2011). RANKL and RANK in Udagawa, N., Takahashi, N., Jimi, E., and and osteoprotegerin regulate Browning, J. L., and Hochman, P. sex hormone-induced breast cancer Matsuzaki, K., Tsurukai, T., Itoh,

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K., Nakagawa, N., Yasuda, H., Goto, White, A., Carragher, D., Parnell, S., osteoclast formation. Nat. Med. 17, Yun, T. J., Chaudhary, P. M., Shu, G. L., M., Tsuda, E., Higashio, K., Gille- Msaki, A., Perkins, N., Lane, P.,Jenk- 1235–1241. Frazer, J. K., Ewings, M. K., Schwartz, spie, M. T., Martin, T. J., and inson, E., Anderson, G., and Caa- Yamaguchi, K., Kinosaki, M., Goto, S. M., Pascual, V., Hood, L. E., and Suda, T. (1999). Osteoblasts/stromal mano, J. H. (2007). Lymphotoxin M., Kobayashi, F., Tsuda, E., Mori- Clark, E. A. (1998). OPG/FDCR-1, cells stimulate osteoclast activation a-dependent and -independent sig- naga, T., and Higashio, K. (1998). a TNF receptor family member, is through expression of osteoclast dif- nals regulate stromal organizer Characterization of structural expressed in lymphoid cells and is ferentiation factor/RANKL but not cell homeostasis during lymph domains of human osteoclastogen- up-regulated by ligating CD40. J. colony-stimulating fac- node organogenesis. Blood 110, esis inhibitory factor. J. Biol. Chem. Immunol. 161, 6113–6121. tor: receptor activator of NF-kappa 1950–1959. 273, 5117–5123. Yun, T. J., Tallquist, M. D., Aicher, B ligand. Bone 25, 517–523. Williamson, E., Bilsborough, J. M., Yasuda, H., Shima, N., Nakagawa, A., Rafferty, K. L., Marshall, A. J., van de Pavert, S. A., Olivier, B. J., Gov- and Viney, J. L. (2002). Regu- N., Yamaguchi, K., Kinosaki, M., Moon, J. J., Ewings, M. E., Mohaupt, erse, G., Vondenhoff, M. F., Greuter, lation of Mucosal Dendritic Cell Mochizuki, S., Tomoyasu, A., Yano, M., Herring, S. W., and Clark, M., Beke, P., Kusser, K., Hopken, Function by Receptor Activator K., Goto, M., Murakami, A., Tsuda, E. A. (2001). Osteoprotegerin, a U. E., Lipp, M., Niederreither, K., of NF-kappaB (RANK)/RANK Lig- E., Morinaga, T., Higashio, K., crucial regulator of bone metabo- Blomhoff, R., Sitnik, K., Agace, W. and Interactions: Impact on Toler- Udagawa, N., Takahashi, N., and lism, also regulates B cell develop- W.,Randall,T.D.,de Jonge,W.J.,and ance Induction. J. Immunol. 169, Suda, T. (1998). Osteoclast dif- ment and function. J. Immunol. 166, Mebius, R. E. (2009). Chemokine 3606–3612. ferentiation factor is a ligand for 1482–1491. CXCL13 is essential for lymph node Witten, P. E., and Huysseune, A. (2009). osteoprotegerin/osteoclastogenesis- initiation and is induced by retinoic A comparative view on mechanisms inhibitory factor and is identical to Conflict of Interest Statement: The acid and neuronal stimulation. Nat. and functions of skeletal remod- TRANCE/RANKL. Proc. Natl. Acad. authors declare that the research was Immunol. 10, 1193–1199. elling in teleost fish, with special Sci. U.S.A. 95, 3597–3602. conducted in the absence of any com- Vondenhoff, M. F.,Greuter, M., Goverse, emphasis on osteoclasts and their Yokota, Y., Mansouri, A., Mori, S., Sug- mercial or financial relationships that G., Elewaut, D., Dewint, P., Ware, function. Biol. Rev. 84, 315–346. awara, S., Adachi, S., Nishikawa, could be construed as a potential con- C. F., Hoorweg, K., Kraal, G., and Wong, B. R., Josien, R., Lee, S. Y., Sauter, S., and Gruss, P. (1999). Develop- flict of interest. Mebius, R. E. (2009). LTbetaR sig- B., Li, H. L., Steinman, R. M., and ment of peripheral lymphoid organs naling induces cytokine expression Choi, Y. (1997a). TRANCE (tumor and natural killer cells depends on Received: 20 June 2012; paper pend- and up-regulates lymphangiogenic necrosis factor [TNF]-related the helix-loop-helix inhibitor Id2. ing published: 13 July 2012; accepted: factors in lymph node anlagen. J. activation-induced cytokine), a new Nature 397, 702–706. 01 August 2012; published online: 03 Immunol. 182, 5439–5445. TNF family member predominantly Yoshida, H., Naito, A., Inoue, J., Satoh, September 2012. Wada, T., Nakashima, T., Hiroshi, expressed in T cells, is a dendritic M., Santee-Cooper, S. M., Ware, C. Citation: Mueller CG and Hess E (2012) N., and Penninger, J. M. (2006). cell-specific survival factor. J. Exp. F., Togawa, A., and Nishikawa, S. Emerging functions of RANKL in lym- RANKL-RANK signaling in osteo- Med. 186, 2075–2080. (2002). Different cytokines induce phoid tissues. Front. Immun. 3:261. doi: clastogenesis and bone disease. Wong, B. R., Rho, J.,Arron, J., Robinson, surface lymphotoxin-alphabeta on 10.3389/fimmu.2012.00261 Trends. Mol. Med. 12, 17–25. E., Orlinick, J., Chao, M., Kalachikov, IL-7 receptor-alpha cells that dif- This article was submitted to Frontiers Walsh, M. C., and Choi, Y. (2003). S., Cayani, E., Bartlett, F. S. III, ferentially engender lymph nodes in Antigen Presenting Cell Biology, a Biology of the TRANCE axis. Frankel, W. N., Lee, S. Y., and Choi, and Peyer’s patches. Immunity 17, specialty of Frontiers in Immunology. Cytokine Growth Factor Rev. 14, Y. (1997b). TRANCE is a novel lig- 823–833. Copyright © 2012 Mueller and Hess. This 251–263. and of the tumor necrosis factor Yoshiki, R., Kabashima, K., Sugita, K., is an open-access article distributed under Wang, R., Zhang, L., Zhang, X., Moreno, receptor family that activates c-Jun Atarashi, K., Shimauchi, T., and the terms of the Creative Commons Attri- J., Celluzzi, C., Tondravi, M., and Shi, N-terminal kinase in T cells. J. Biol. Tokura, Y. (2009). IL-10-producing bution License, which permits use, distri- Y. (2002). Regulation of activation- Chem. 272, 25190–25194. Langerhans cells and regulatory T bution and reproduction in other forums, induced receptor activator of NF- Xiong, J., Onal, M., Jilka, R. L., cells are responsible for depressed provided the original authors and source kappaB ligand (RANKL) expression Weinstein, R. S., Manolagas, S. contact hypersensitivity in grafted are credited and subject to any copy- in T cells. Eur. J. Immunol. 32, C., and O’Brien, C. A. (2011). skin. J. Invest. Dermatol. 129, right notices concerning any third-party 1090–1098. Matrix-embedded cells control 705–713. graphics etc.

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