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Lymph Node Development Ontogeny of Stromal Organizer Cells During Ontogeny of Stromal Organizer Cells during Lymph Node Development Cécile Bénézech, Andrea White, Emma Mader, Karine Serre, Sonia Parnell, Klaus Pfeffer, Carl F. Ware, Graham This information is current as Anderson and Jorge H. Caamaño of September 28, 2021. J Immunol 2010; 184:4521-4530; Prepublished online 17 March 2010; doi: 10.4049/jimmunol.0903113 http://www.jimmunol.org/content/184/8/4521 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2010/03/15/jimmunol.090311 Material 3.DC1 http://www.jimmunol.org/ References This article cites 47 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/184/8/4521.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 28, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Ontogeny of Stromal Organizer Cells during Lymph Node Development Ce´cile Be´ne´zech,* Andrea White,* Emma Mader,* Karine Serre,* Sonia Parnell,* Klaus Pfeffer,† Carl F. Ware,‡ Graham Anderson,* and Jorge H. Caaman˜o* The development of secondary lymphoid organs, such as lymph nodes (LNs), in the embryo results from the reciprocal action between lymphoid tissue inducer (LTi) cells and stromal cells. However, the initial events inducing LN anlagen formation before the LTi stromal cells cross-talk interactions take place are not fully elucidated. In this study, we show that the inguinal LN anlagen in mouse embryos developed from mesenchymal cells surrounding the lymph sacs, spherical structures of endothelial cells that bud from veins. Using inguinal and mesenteric LNs (mLNs), we provide evidence supporting a two-step maturation model for stromal cells: first, ICAM-12VCAM-12 mesenchymal precursor cells become ICAM-1intVCAM-1int cells, in a process independent of LTi cells and lymphotoxin b receptor (LTbR) signaling. The second step involves the maturation of ICAM-1intVCAM-1int cells to ICAM-1high Downloaded from VCAM-1high mucosal addressin cell adhesion molecule-1+ organizer cells and depends on both LTi cells and LTbR. Addition of aLTbR agonist to LN organ cultures was sufficient to induce ICAM-1intVCAM-1int cells to mature. In LtbR2/2 embryos, both inguinal and mLN stromal cells showed a block at the ICAM-1intVCAM-1int stage, and, contrary to inguinal LNs, mLNs persist longer and contained LTi cells, which correlated with the sustained gene expression of Il-7,Cxcl13, and, to a lesser degree, Ccl21. Taken together, these results highlight the importance of the signals and cellular interactions that induce the maturation of stromal cells and ultimately lead to the formation of lymphoid tissues. The Journal of Immunology, 2010, 184: 4521–4530. http://www.jimmunol.org/ ymph nodes (LNs) are specialized structures situated at VCAM-1, chemokines, and cytokines by the stromal cells (1–3). strategic sites in the body along the lymphatic vasculature However, the early events regulating LN anlagen formation re- L network. They enable filtration of Ags and pathogens and main unknown. provide a site for Ag presentation to lymphocytes and induction of LN formation is tightly linked to the development of the lym- adaptive immune responses. LN development is not fully eluci- phatic system and in particular to the formation of lymph sacs. dated, although several studies have reported on the role of lym- Although these events have been described a century ago, our phoid tissue inducer (LTi) cells at late stages of LN formation. understanding is still limited. In 1902, Sabin (4, 5) proposed that by guest on September 28, 2021 Recruitment of LTi cells that express the TNF family molecule lymph sacs form from the budding and sprouting of endothelial lymphotoxin a1b2 to the LN anlagen allows engagement of cells from veins. In contrast, Huntington and McClure (6) sug- lymphotoxin b receptor (LTbR)-expressing stromal cells. Sub- gested that lymph sacs develop from mesenchymal cells first, sequently, activation of two different pathways of the NF-kB before venous endothelial sprouting occurs from the newly formed transcription factor results in expression of high levels of ICAM-1, lymph sacs. More recently, the use of markers specific for lym- phatic endothelial cells, such as VEGFR3 (7), Prox-1 (8), and the hyaluronic acid receptor Lyve-1, showed that Lyve-1+Prox-1+ *School of Immunity and Infection, Institute for BioMedical Research-Medical Re- endothelial cells located in the anterior cardinal vein bud around search Council Centre for Immune Regulation, College of Medical and Dental Sci- † embryonic day (E) 10.5–11.5 to form a lymph sac under the ences, University of Birmingham, Birmingham, United Kingdom; Institut fur Medizinische Mikrobiologie und Krankenhaushygiene, Heinrich-Heine-University, guidance of VEGFC signals (9). These data are in agreement with Du¨sseldorf, Germany; and ‡La Jolla Institute for Allergy and Immunology, La Jolla, Sabin’s model (10), which suggested that stromal cells derive CA 92037 from the lymph sac, which itself has an endothelial origin. In- Received for publication September 23, 2009. Accepted for publication February 11, terestingly, a recent report showed that Prox-12/2 mouse embryos 2010. failed to develop lymph sacs, although they were still able to form This work was supported by a Biotechnology and Biological Sciences Research Council project grant (to J.H.C. and G.A). Work in the laboratory of C.F.W. was primitive LN anlagen, indicating that endothelial cells are not supported by National Institutes of Health Grant AI33068. E.M. is the recipient of required to form the LN primordium and that the LN anlage de- a Medical Research Council Doctoral Training Account Ph.D. studentship. rives from distinct cell types (11). Address correspondence and reprint requests to Dr. Jorge H. Caaman˜o, IBR-MRC We have previously reported on the isolation of inguinal LN Centre for Immune Regulation, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, U.K. E-mail address: [email protected] (iLN) anlagen prior to the recruitment of LTi cells (12). In this The online version of this article contains supplemental material. study, we report on the sequence of events leading to the forma- tion of iLN and mesenteric LN (mLN) anlagen in the mouse Abbreviations used in this paper: Ct, cycle threshold; E, embryonic day; iLN, in- guinal lymph node; I2V2, negative for ICAM-1 and VCAM-1; I+V2, ICAM-1 embryo. Our observations indicate that iLN anlage develops at the single-positive; IhighVhigh, high expression of ICAM-1 and VCAM-1; IintVint, inter- site of interactions between the budding endothelium and sur- mediate levels of ICAM-1 and VCAM-1; LN, lymph node; LTbR, lymphotoxin b receptor; LTi, lymphoid tissue inducer; MAdCAM-1, mucosal addressin cell adhe- rounding layers of mesenchymal cells that appear to invade the sion molecule-1; mLN, mesenteric lymph node; NA, numerical aperture; PDGFR, former. Combining confocal microscopy and FACS analysis of platelet-derived growth factor receptor; qPCR, quantitative PCR; RANKL, receptor E15 iLNs, we show the appearance of the very first stromal cells activator for NF-kB ligand; WT, wild-type. coexpressing mesenchymal markers, like platelet-derived growth Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 factor receptor (PDGFR)a, and the stromal markers ICAM-1 or www.jimmunol.org/cgi/doi/10.4049/jimmunol.0903113 4522 STROMAL CELL MATURATION DURING LYMPH NODE DEVELOPMENT gp38/podoplanin. These cells, characterized by their intermediate from the Ct of the target gene, and the relative amount was calculated as 2DC levels of expression of ICAM-1 and VCAM-1 (IintVint), seem to 2 t. Means of triplicate reactions (multiply 1000-fold) were represented, give rise to ICAM-1highVCAM-1high (IhighVhigh) mucosal addressin and data shown are representative of at least two separate cell-sorting experiments. Primer sequences are shown in Supplemental Fig. 1. cell adhesion molecule-1 (MAdCAM-1)+ stromal organizer cells. This is supported by our findings using an in vitro organ culture Immunofluorescence stainings b system with an agonistic anti-LT R Ab. The stromal cell matura- For tissue-section stainings, iLNs and mLNs were isolated and embedded in tion correlates with a gradual increase in mRNA levels of cytokine OCTcompound(TissueTek,Torrance,CA),thenfrozenin liquid nitrogen.Six- and chemokine genes. We also show that LTbR and LTi cells are micrometer sections of tissue were cut and fixed in acetone. Abs used were a required for the IintVint cells to become IhighVhigh organizer cells. gp38/podoplanin 8.1.1, ICAM-1–FITC clone YN1/1.7.4, PDGFR clone 2/2 APA5, CD44-FITC clone IM7, receptor activator for NF-kB ligand (RANKL)- Finally, our results demonstrate that in E17 LtbR mLN, LTi biotin clone IK22/5, MAdCAM-biotin clone MECA-367 (eBioscience), col- cells are present and that Cxcl13, Il-7, and lower levels of Ccl21 are lagen type I (Chemicon International, Temecula, CA), laminin a5 (rat; gift of still expressed, indicating that LTbR is not fully necessary for the A. Zapata, Complutense University, Madrid, Spain), perlecan (rat; gift of initial recruitment of LTi cells to the mLNs.
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