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* Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021;
Department of Microbiology and Immunology and
Graduate Program in Immunology and Microbial Pathogenesis, Weill Medical College of Cornell University, New York, NY 10021; and
Department of Pathology, Yale University, New Haven, CT 06520
The lymph node vasculature is essential to immune function, but mechanisms regulating lymph node vascular maintenance and growth are not well understood. Vascular endothelial growth factor (VEGF) is an important mediator of lymph node endothelial cell proliferation in stimulated lymph nodes. It is expressed basally in lymph nodes and up-regulated upon lymph node stimulation, but the identity of VEGF-expressing cells in lymph nodes is not known. We show that, at homeostasis, fibroblast-type reticular stromal cells (FRC) in the T zone and medullary cords are the principal VEGF-expressing cells in lymph nodes and that VEGF plays a role in maintaining endothelial cell proliferation, although peripheral node addressin (PNAd)+ endothelial cells are less sensitive than PNAd– endothelial cells to VEGF blockade. Lymphotoxin β receptor (LTβR) blockade reduces homeostatic VEGF levels and endothelial cell proliferation, and LTβR stimulation of murine fibroblast-type cells up-regulates VEGF expression, suggesting that LTβR signals on FRC regulate lymph node VEGF levels and, thereby, lymph node endothelial cell proliferation. At the initiation of immune responses, FRC remain the principal VEGF mRNA-expressing cells in lymph nodes, suggesting that FRC may play an important role in regulating vascular growth in stimulated nodes. In stimulated nodes, VEGF regulates the proliferation and expansion of both PNAd+ and PNAd– endothelial cells. Taken together, these data suggest a role for FRC as paracrine regulators of lymph node endothelial cells and suggest that modulation of FRC VEGF expression may be a means to regulate lymph node vascularity and, potentially, immune function.
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1 This work was funded by National Institute of Allergy and Infectious Diseases R01-AI069800, Arthritis Foundation Investigator Award and Lupus Research Institute award (T.L.), T32-AI007621 (E.E.), CRI Tumor Immunology Predoctoral Fellowship (T.T.), and T32-AR007517 (A.C.).
2 S.C. and E.H.E. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Theresa T. Lu, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address: lut{at}hss.edu
4 Abbreviations used in this paper: VEGF, vascular endothelial growth factor; β-gal, β-galactosidase; FRC, fibroblast-type reticular stromal cells; HEV, high endothelial venules; LTβR, lymphotoxin β receptor; PNAd, peripheral node addressin; VE, vascular endothelial; LIGHT, lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry mediator on T cells.
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