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CCR7 Signaling Inhibits T Cell Proliferation¹

Ekkehard Ziegler^*, Martin Oberbarnscheidt^*, Silvia Bulfone-Paus, Reinhold Förster, Ulrich Kunzendorf^2,* and Stefan Krautwald^*

^* Department of Nephrology and Hypertension, University of Kiel, Kiel Germany; Department of Immunology and Cell Biology, Research Center Borstel, Borstel, Germany; and Institute of Immunology, Hannover Medical School, Hannover, Germany

CCR7 and its ligands, CCL19 and CCL21, are responsible for directing the migration of T cells and dendritic cells into lymph nodes, where these cells play an important role in the initiation of the immune response. Recently, we have shown that systemic application of CCL19-IgG is able to inhibit the colocalization of T cells and dendritic cells within secondary lymphoid organs, resulting in pronounced immunosuppression with reduced allograft rejection after organ transplantation. In this study, we demonstrate that the application of sustained high concentrations of either soluble or immobilized CCL19 and CCL21 elicits an inhibitory program in T cells. We show that these ligands specifically interfere with cell proliferation and IL-2 secretion of CCR7⁺ cells. This could be demonstrated for human and murine T cells and was valid for both CD4⁺ and CD8⁺ T cells. In contrast, CCL19 had no inhibitory effect on T cells from CCR7 knockout mice, but CCR7^–/– T cells showed a proliferative response upon TCR-stimulation similar to that of CCL19-treated wild-type cells. Furthermore, the inhibition of proliferation is associated with delayed degradation of the cyclin-dependent kinase (CDK) inhibitor p27^Kip1 and the down-regulation of CDK1. This shows that CCR7 signaling is linked to cell cycle control and that sustained engagement of CCR7, either by high concentrations of soluble ligands or by high density of immobilized ligands, is capable of inducing cell cycle arrest in TCR-stimulated cells. Thus, CCR7, a chemokine receptor that has been demonstrated to play an essential role during activation of the immune response, is also competent to directly inhibit T cell proliferation.

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 study has been supported by a grant from the Medical Faculty of the University of Kiel, Kiel Germany.

² Address correspondence and reprint requests to Dr. Ulrich Kunzendorf, Department of Nephrology and Hypertension, University of Kiel, Schittenhelmstrasse 12, 24105 Kiel, Germany. E-mail address: kunzendorf{at}nephro.uni-kiel.de

³ Abbreviations used in this paper: DC, dendritic cell; CDK, cyclin-dependent kinase; CHO, Chinese hamster ovary; hIgG, human IgG.