CC Chemokine Receptor 7–dependent and –independent Pathways for Lymphocyte Homing

Abstract

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-αi-dependent, CCR7-CCL19/CCL21-independent mechanism for lymphocyte homing through HEVs which is strongly augmented in the presence of FTY720.

Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

“…Mice lacking CCR7 show impaired ability to maintain tolerance to peripheral antigens as they develop signs of autoimmunity [70,71]: they exhibit lymphocyte infiltration in peripheral organs, elevated levels of circulating antibodies towards tissue-specific antigens, IgG deposition around the renal glomeruli, and increased susceptibility to inducible diabetes, and they can spontaneously develop chronic autoimmune renal disease [70]. These mice, as well as those lacking CCL19 and CCL21 (plt mice), which lack recognizable T cells zones within all LNs [72][73][74][75][76], can still mount strong cellular immune responses [6]. This is consistent with the mounting evidence that although B cell responses require their residence in functional lymph nodes, T cell immunity apparently does not, and T cells can be activated in the spleen or even liver when lymph nodes are absent or dysfunctional (reviewed in [77]).…”

Sphingosine 1-Phosphate Receptors Regulate Chemokine-Driven Transendothelial Migration of Lymph Node but Not Splenic T Cells

“…Previous reports demonstrated that S1P and FTY720 sensitize or enhance peripheral T cell migration to chemokines suggesting that sequestration of T cells within PLNs is dependent on both chemokine and S1PR engagement on the T cell surface (9,10,16 readily enter secondary lymphoid organs and migrate to appropriate T cell compartments. Conversely, in a variety of studies, a lack of chemokines or chemokine receptors prevents T cell trafficking and accumulation in the PLN, even if S1PR are stimulated (9,10,17). Our current results indicate that peripheral splenic T cells show enhanced migration to chemokines in the presence of S1PR stimulation, but can still migrate if S1P agonists are absent or if S1P 1 is desensitized or down-modulated.…”

“…It is important to acknowledge that a limitation to our results is the use of vascular endothelial cells, because murine lymphatic endothelial cells and lines are not readily and reproducibly available, and with uncertainty as to whether those cells reliably reproduce the in vivo environment. Specific homophilic and heterophilic receptor interactions between leukocytes and endothelial cells result in both outside-in and inside-out signaling, initiating a complex process that results in transient dissolution and separation of endothelial adherens junctions to permit leukocyte transmural migration (17,18,27). The data here suggest that S1PR function is required for this step in T cell PLN egress.…”

A new immunosuppressant, FTY720, in canine kidney transplantation: effect of single-drug, induction and combination treatments

“…Chiba et al and Brinkmann et al reported that the precise mechanisms of PBL reduction by FTY720, at concentration orders of nanomoles per liter, have been considered to be accelerated lymphocyte homing/trafficking to lymphoid tissues [5,6,7,81. Suzuki and others, in in vitro studies with rat spleen cells, human peripheral blood cells, and cancer cell lines, have found that, at a serum concentration of 2 pmol/l (700 ng/ml) or more, FTY720 induces apoptotic cell death resulting in PBL reduction [9,10,11,12,13,141.…”

“…This effect is thought to be caused by enhanced lymphocyte homing, at concentration orders of nanomoles per liter [l, 2, 3,4], via augmented expression of adhesion molecules, Gprotein-coupled chemokine receptors, and their ligands on the lymphocytes and/or high endothelial venules (HEVs) of lymph nodes (LNs) and Peyer's patches (PPs) [5,6,7,81. When FTY720 is administered at higher concentrations [i.e., at more than 2 or 4 pmol/l (700 or 1,400 ngiml)], T cells from MRL/lpr mice, rat spleen cells, human peripheral blood cells, and/or other cell lines, including cancer cells, undergo apoptosis [3, 9, 10, 11, 12, 13, 141. In experimental allogenic organ transplantation studies, FTY720 exhibited mild immunosuppression as a single-drug treatment and, when combined with conventional drugs, had synergistic immunomodulatory activity with or without adverse events [9,15,16,17,18,19,20,21,22,23,24,251.…”