CC chemokine receptor 7-dependent and -independent pathways for lymphocyte homing: modulation by FTY720.
Cognate interaction of chemokine receptor CCR7 on lymphocytes with its ligands CCL19 and CCL21 expressed on high endothelial venules (HEVs) is essential for effective migration of T and B cells across HEVs into secondary lymphoid organs. Plt mice, which lack expression of CCL19 and CCL21-ser, both ligands for CCR7 on HEVs, as well as CCR7-deficient mice, have a defective cell migration and reduced homing of lymphocytes. FTY720, a novel immunosuppressant, causes a reduction of lymphocytes in peripheral blood and tissues and their sequestration into lymphoid tissues. In this study we demonstrate that FTY720 rescues the homing defect in both CCR7(-/-) mice and plt mice. After FTY720 treatment, the number of CD4(+) and CD8(+) T cells as well as B cells in peripheral blood is reduced while pertussis toxin-sensitive homing into peripheral lymph nodes, mesenteric lymph node, and Peyer's patches is increased. Immunohistology demonstrates that FTY720 enables these cells to enter lymphoid tissue through HEVs. Thus, our data suggest an alternative G-alpha(i)-dependent, CCR7-CCL19/CCL21-independent mechanism for lymphocyte homing through HEVs which is strongly augmented in the presence of FTY720.
Henning
G
G
Section of Experimental Surgery and Immunology, University Clinic for Surgery and Nikolaus-Fiebiger-Zentrum, 91054 Erlangen, Germany.
Ohl
L
L
Junt
T
T
Reiterer
P
P
Brinkmann
V
V
Nakano
H
H
Hohenberger
W
W
Lipp
M
M
Förster
R
R
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000276:immunology; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011409:Propylene Glycols / Q000276:immunology / Q000494:pharmacology; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000276:immunology*; D013110:Sphingosine / Q000031:analogs & derivatives
C515461:Ccl19 protein, mouse; C515479:Ccl21c protein, mouse; C515371:Ccr7 protein, mouse; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D019742:Chemokines, CC; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine