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* Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; and
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
In the paracortex of the lymph node (LN), T zone fibroblastic reticular cells (TRCs) orchestrate an immune response by guiding lymphocyte migration both physically, by creating three-dimensional (3D) cell networks, and chemically, by secreting the chemokines CCL19 and CCL21 that direct interactions between CCR7-expressing cells, including mature dendritic cells and naive T cells. TRCs also enwrap matrix-based conduits that transport fluid from the subcapsular sinus to high endothelial venules, and fluid flow through the draining LN rapidly increases upon tissue injury or inflammation. To determine whether fluid flow affects TRC organization or function within a 3D network, we regenerated the 3D LN T zone stromal network by culturing murine TRC clones within a macroporous polyurethane scaffold containing type I collagen and Matrigel and applying slow interstitial flow (1–23 µm/min). We show that the 3D environment and slow interstitial flow are important regulators of TRC morphology, organization, and CCL21 secretion. Without flow, CCL21 expression could not be detected. Furthermore, when flow through the LN was blocked in mice in vivo, CCL21 gene expression was down-regulated within 2 h. These results highlight the importance of lymph flow as a homeostatic regulator of constitutive TRC activity and introduce the concept that increased lymph flow may act as an early inflammatory cue to enhance CCL21 expression by TRCs, thereby ensuring efficient immune cell trafficking, lymph sampling, and immune response induction.
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 Funding was provided by the Swiss National Science Foundation (107602) to M.A.S. and (PPOOA-68805 and PPOOA-116896) to S.A.L., as well as by Boehringer Ingelheim to S.S.
2 S.S. and M.R.B. contributed equally to this work.
3 S.A.L. and M.A.S. contributed equally to this work.
4 Address correspondence and reprint requests to Dr. Melody A. Swartz, Institute of Bioengineering, School of Life Sciences, Laboratory of Mechanobiology and Morphology, Station 15, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland. E-mail address: melody.swartz{at}epfl.ch or Dr. Sanjiv A. Luther, Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, 1066 Epalinges, Switzerland. E-mail address: sluther{at}unil.ch
5 Abbreviations used in this paper: LN, lymph node; 2D, two dimension(al); 3D, three dimension(al); dyn, dyne; ECM, extracellular matrix; HEV, high endothelial venule; LT, lymphotoxin; PDGF-R, platelet-derived growth factor receptor; PU, polyurethane; TRC, T zone fibroblastic reticular cell.
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