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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0802167v1 183/3/1767    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Podgrabinska, S. Articles by Skobe, M. PubMed PubMed Citation Articles by Podgrabinska, S. Articles by Skobe, M.

Inflamed Lymphatic Endothelium Suppresses Dendritic Cell Maturation and Function via Mac-1/ICAM-1-Dependent Mechanism¹

Simona Podgrabinska^*, Okebugwu Kamalu, Lloyd Mayer, Motomu Shimaoka, Hans Snoeck, Gwendalyn J. Randolph^, and Mihaela Skobe^2,*

^* Department of Oncological Sciences, Immunology Institute, Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029; and Immune Disease Institute, Harvard Medical School, Boston, MA 02115

The lymphatic system is essential for the generation of immune responses by facilitating immune cell trafficking to lymph nodes. Dendritic cells (DCs), the most potent APCs, exit tissues via lymphatic vessels, but the mechanisms of interaction between DCs and the lymphatic endothelium and the potential implications of these interactions for immune responses are poorly understood. In this study, we demonstrate that lymphatic endothelial cells (LECs) modulate the maturation and function of DCs. Direct contact of human monocyte-derived DCs with an inflamed, TNF--stimulated lymphatic endothelium reduced expression of the costimulatory molecule CD86 by DCs and suppressed the ability of DCs to induce T cell proliferation. These effects were dependent on adhesive interactions between DCs and LECs that were mediated by the binding of Mac-1 on DCs to ICAM-1 on LECs. Importantly, the suppressive effects of the lymphatic endothelium on DCs were observed only in the absence of pathogen-derived signals. In vivo, DCs that migrated to the draining lymph nodes upon inflammatory stimuli, but in the absence of a pathogen, showed increased levels of CD86 expression in ICAM-1-deficient mice. Together, these data demonstrate a direct role of LECs in the modulation of immune response and suggest a function of the lymphatic endothelium in preventing undesired immune reactions in inflammatory conditions.

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 funds from the Emerald Foundation (to M.S.) and by U.S. Department of Defense Grant BC044819 (to M.S.). Confocal laser scanning microscopy was performed at the Mount Sinai School of Medicine-Microscopy Shared Resource Facility supported with funding from National Institutes of Health-National Cancer Institute Shared Resources Grant 5R24 CA095823-04, National Science Foundation Major Research Instrumentation Grant DBI-9724504, and National Institutes of Health Shared Instrumentation Grant 1 S10 RR0 9145-01.

² Address correspondence and reprint requests to Dr. Mihaela Skobe, Department of Oncological Sciences, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1130, New York, NY 10029. E-mail address: mihaela.skobe{at}mssm.edu

³ Abbreviations used in this paper: DC, dendritic cell; BMDC, bone marrow-derived dendritic cell; imDC, immature DC; KO, knockout; LEC, lymphatic endothelial cell; LN, lymph node; mDC, mature DC; MFI, mean fluorescence intensity; PAMP, pathogen-associated molecular pattern; VEGF, vascular endothelial growth factor; WT, wild type.

⁴ The online version of this article contains supplemental material.