CCR7 signaling inhibits T cell proliferation.
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.
Ziegler
Ekkehard
E
Department of Nephrology and Hypertension, University of Kiel, Kiel, Germany.
Oberbarnscheidt
Martin
M
Bulfone-Paus
Silvia
S
Förster
Reinhold
R
Kunzendorf
Ulrich
U
Krautwald
Stefan
S
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016203:CDC2 Protein Kinase / Q000276:immunology / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D054415:Chemokine CCL19 / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D054421:Chemokine CCL21 / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance / Q000187:drug effects / Q000235:genetics; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016377:Organ Transplantation; D054400:Receptors, CCR7 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology; D014184:Transplantation, Homologous
C515461:Ccl19 protein, mouse; C515371:Ccr7 protein, mouse; C493961:Cdkn1b protein, mouse; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D007074:Immunoglobulin G; D007376:Interleukin-2; D054400:Receptors, CCR7; D011993:Recombinant Fusion Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016203:CDC2 Protein Kinase