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Dynamic Modulation of CCR7 Expression and Function on Naive T Lymphocytes In Vivo¹

Department of Biochemistry, University of Lausanne, Epalinges, Switzerland

The chemokine receptor CCR7 is critical for the recirculation of naive T cells. It is required for T cell entry into secondary lymphoid organs (SLO) and for T cell motility and retention within these organs. How CCR7 activity is regulated during these processes in vivo is poorly understood. Here we show strong modulation of CCR7 surface expression and occupancy by the two CCR7 ligands, both in vitro and in vivo. In contrast to blood, T cells in SLO had most surface CCR7 occupied with CCL19, presumably leading to continuous signaling and cell motility. Both ligands triggered CCR7 internalization in vivo as shown in Ccl19^–/– and plt/plt mice. Importantly, CCR7 occupancy and down-regulation led to strongly impaired chemotactic responses, an effect reversible by CCR7 resensitization. Therefore, during their recirculation, T cells cycle between states of free CCR7 with high ligand sensitivity in blood and occupied CCR7 associated with continual signaling and reduced ligand sensitivity within SLO. We propose that these two states of CCR7 are important to allow the various functions CCR7 plays in T cell recirculation.

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 the Swiss National Science Foundation (PPOOA-68805 and PPOOA-116896 to S.A.L.).

M.R.B. did all experiments and wrote the manuscript; A.L. set up the chemotaxis assay and helped with the transfer experiments; T.K.A.L. set up the CCR7 and CCL19-Fc staining protocols; S.A.L. designed and directed the study and wrote the manuscript; and all authors critically reviewed the manuscript.

² Address correspondence and reprint requests to Dr. Sanjiv A. Luther, Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, 1066 Epalinges, Switzerland. E-mail address: sanjiv.luther{at}unil.ch

³ Abbreviations used in this paper: SLO, secondary lymphoid organs; LN, lymph nodes; DCs, dendritic cells; TRC, T zone reticular cells; HEV, high endothelial venules; plt, paucity of lymph node T cell; MFI, mean fluorescent index.