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* Department of Molecular Cell Biology and Immunology, VU (Vrije Universiteit) University Medical Center, Amsterdam, The Netherlands;
Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent, Belgium; and
Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037
The formation of lymph nodes is a complex process crucially controlled through triggering of LTβR on mesenchymal cells by LT
1β2 expressing lymphoid tissue inducer (LTi) cells. This leads to the induction of chemokines to attract more hematopoietic cells and adhesion molecules to retain them. In this study, we show that the extravasation of the first hematopoietic cells at future lymph node locations occurs independently of LT and that these cells, expressing TNF-related activation-induced cytokine (TRANCE), are the earliest LTi cells. By paracrine signaling the first expression of LT1β2 is induced. Subsequent LTβR triggering on mesenchymal cells leads to their differentiation to stromal organizers, which now also start to express TRANCE, IL-7, as well as VEGF-C, in addition to the induced adhesion molecules and chemokines. Both TRANCE and IL-7 will further induce the expression of LT1β2 on newly arrived immature LTi cells, resulting in more LTβR triggering, generating a positive feedback loop. Thus, LTβR triggering by LTi cells during lymph node development creates a local environment to which hematopoietic precursors are attracted and where they locally differentiate into fully mature, LT1β2 expressing, LTi cells. Furthermore, the same signals may regulate lymphangiogenesis to the lymph node through induction of VEGF-C.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a VICI Grant (918.56.612) to R.E.M and a Genomics Grant (050-10-120) to M.V. from the Netherlands Organization for Scientific Research.
M.V. and R.M. designed the research and analyzed and interpreted the data; M.V., M.G., G.G., D.E., P.W., and K.H. collected the data, while M.V. and G.G. performed the statistical analyses; C.W. contributed vital reagents to this study; and M.V., G.K., and R.M. drafted the manuscript.
2 Address correspondence and reprint requests to Dr. Reina E. Mebius, Department of Molecular Cell Biology and Immunology, VU (Vrije Universiteit) University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail address: r.mebius{at}vumc.nl
3 Abbreviations used in this paper: LN, lymph node; LTi, lymphoid tissue inducer; LT1β2, lymphotoxin-1β2; LTβR, lymphotoxin β receptor; WT, wild type; MAdCAM-1, anti-mucosal addressin cell adhesion molecule-1; LT, lymphotoxin ; MEF, mouse embryonic fibroblasts; rMLN, rudimentary mesenteric LN; ALN, axillary LN; BLN, brachial LN; LEC, lymphatic endothelial cell; TRANCE, TNF-related activation-induced cytokine.
4 The online version of this article contains supplemental material.
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