Dynamic modulation of CCR7 expression and function on naive T lymphocytes in vivo.
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.
Britschgi
Mirjam R
MR
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Link
Alexander
A
Lissandrin
Tonje Katrine A
TK
Luther
Sanjiv A
SA
D000818:Animals; D054415:Chemokine CCL19 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002633:Chemotaxis / Q000235:genetics / Q000276:immunology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D054400:Receptors, CCR7 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
C515461:Ccl19 protein, mouse; C515371:Ccr7 protein, mouse; D054415:Chemokine CCL19; D054400:Receptors, CCR7