The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20080752
The Journal of Experimental Medicine, Vol. 206, No. 1, 233-248
The Rockefeller University Press, 0022-1007 $30.00
© Gräbner et al.
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ARTICLE

 Lymphotoxin β receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE–/– mice

Rolf Gräbner1, Katharina Lötzer1, Sandra Döpping1, Markus Hildner1, Dörte Radke1,3, Michael Beer1, Rainer Spanbroek1, Beatrix Lippert1, Catherine A. Reardon4, Godfrey S. Getz4, Yang-Xin Fu4, Thomas Hehlgans5, Reina E. Mebius6, Michael van der Wall2, Dagmar Kruspe7, Christoph Englert7, Agnes Lovas8, Desheng Hu8, Gwendalyn J. Randolph9, Falk Weih8, and Andreas J.R. Habenicht1

1 Institute for Vascular Medicine, 2 Animal Research Institute, Friedrich Schiller University of Jena, 07743 Jena, Germany
3 Leibniz-Institute for Natural Product Research and Infection Biology, Hans-Knoell-Institute, 07745 Jena, Germany
4 Department of Pathology, University of Chicago, Chicago, IL 60637
5 Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany
6 Department of Molecular Cell Biology and Immunology, Vrje Universiteit Medical Center, 1007 MB Amsterdam, Netherlands
7 Research Group Molecular Genetics, 8 Research Group Immunology, Leibniz-Institute for Age Research, Fritz-Lipmann-Institute, 07745 Jena, Germany
9 Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029

CORRESPONDENCE Andreas J.R. Habenicht: andreas.habenicht{at}mti.uni-jena.de

Atherosclerosis involves a macrophage-rich inflammation in the aortic intima. It is increasingly recognized that this intimal inflammation is paralleled over time by a distinct inflammatory reaction in adjacent adventitia. Though cross talk between the coordinated inflammatory foci in the intima and the adventitia seems implicit, the mechanism(s) underlying their communication is unclear. Here, using detailed imaging analysis, microarray analyses, laser-capture microdissection, adoptive lymphocyte transfers, and functional blocking studies, we undertook to identify this mechanism. We show that in aged apoE–/– mice, medial smooth muscle cells (SMCs) beneath intimal plaques in abdominal aortae become activated through lymphotoxin β receptor (LTβR) to express the lymphorganogenic chemokines CXCL13 and CCL21. These signals in turn trigger the development of elaborate bona fide adventitial aortic tertiary lymphoid organs (ATLOs) containing functional conduit meshworks, germinal centers within B cell follicles, clusters of plasma cells, high endothelial venules (HEVs) in T cell areas, and a high proportion of T regulatory cells. Treatment of apoE–/– mice with LTβR-Ig to interrupt LTβR signaling in SMCs strongly reduced HEV abundance, CXCL13, and CCL21 expression, and disrupted the structure and maintenance of ATLOs. Thus, the LTβR pathway has a major role in shaping the immunological characteristics and overall integrity of the arterial wall.

Abbreviations used: {alpha}-LTβR, agonistic LTβR antibody; AAA, abdominal aorta aneurysm; ATLO, aorta tertiary lymphoid organ; DN, double-negative; FDC, follicular DC; GC, germinal center; GO, gene ontology; HEV, high endothelial venule; LCM, laser-capture microdissection; LTβ, lymphotoxin β chain; LTβR, LTβ receptor; MAdCAM-1, mucosal addressin cell adhesion molecule 1; PNA, peanut agglutinin; PNAd, peripheral LN addressin; SLO, secondary lymphoid organ; SMA, smooth muscle actin; TLO, tertiary lymphoid organ; TNFRSF1A, tumor necrosis factor receptor superfamily, member 1A.

© 2009 Gräbner et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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