Variations in Gnai2 and Rgs1 expression affect chemokine receptor signaling and the organization of secondary lymphoid organs

Abstract Migration of dendritic cells (DCs) into tissues and secondary lymphoid organs plays a crucial role in the initiation of innate and adaptive immunity. In this article, we show that cyclosporin A (CsA) impairs the migration of DCs both in vitro and in vivo. Exposure of DCs to clinical concentrations of CsA neither induces apoptosis nor alters development but does impair cytokine secretion, chemokine receptor expression, and migration. In vitro, CsA impairs the migration of mouse bone marrow–derived DCs toward macrophage inflammatory protein-3β (MIP-3β) and induces them to retain responsiveness to MIP-1α after lipopolysaccharide (LPS)–stimulated DC maturation, while in vivo administration of CsA inhibits the migration of DCs out of skin and into the secondary lymphoid organs. CsA impairs chemokine receptor and cyclooxygenase-2 (COX-2) expression normally triggered in LPS-stimulated DCs; administration of exogenous prostaglandin E2 (PGE2) reverses the effects of CsA on chemokine receptor expression and DC migration. Inhibition of nuclear factor–κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway signaling by CsA may be responsible for the CsA-mediated effects on the regulation of chemokine receptor and cyclooxygenase-2 (COX-2) expression. Impairment of DC migration due to inhibition of PGE2 production and regulation of chemokine receptor expression may contribute, in part, to CsA-mediated immunosuppression.

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Upregulation of CC Chemokine Receptor 7 (CCR7) Enables Migration of Xenogeneic Human Adipose-Derived Mesenchymal Stem Cells to Rat Secondary Lymphoid Organs

Medical Science Monitor ◽

10.12659/msm.902690 ◽

2016 ◽

Vol 22 ◽

pp. 5206-5217 ◽

Cited By ~ 5

Author(s):

Tian Ma ◽

Shao-Liang Luan ◽

Hong Huang ◽

Xing-Kun Sun ◽

Yan-Mei Yang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Chemokine Receptor ◽

Lymphoid Organs ◽

Cc Chemokine ◽

Secondary Lymphoid Organs ◽

Cc Chemokine Receptor 7

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Cooperative function of CCR7 and lymphotoxin in the formation of a lymphoma-permissive niche within murine secondary lymphoid organs

Blood ◽

10.1182/blood-2010-11-321265 ◽

2011 ◽

Vol 118 (4) ◽

pp. 1020-1033 ◽

Cited By ~ 35

Author(s):

Armin Rehm ◽

Angela Mensen ◽

Kristina Schradi ◽

Kerstin Gerlach ◽

Stefanie Wittstock ◽

...

Keyword(s):

Chemokine Receptor ◽

Cross Talk ◽

Stromal Cells ◽

Lymphoid Organs ◽

Receptor Expression ◽

Lymphoma Cells ◽

Significant Survival ◽

Human Lymphoma ◽

Β Receptor ◽

Secondary Lymphoid Organs

Abstract Lymphoma cell survival and progression are putatively dependent on a specific microanatomic localization within secondary lymphoid organs. Despite compelling data correlating homeostatic chemokine receptor expression and human lymphoma pathogenesis, genetic models that either mimic lymphoma dissemination or dissect a crosstalk of lymphoma and stromal cells are missing. Applying the genetically tractable Eμ-Myc transgenic mouse model, we show that the chemokine receptor CCR7 regulates Eμ-Myc lymphoma homing to lymph nodes and distinctive microanatomic sites of the spleen. CCR7-controlled access of lymphoma cells to the splenic T-cell zone led to a significant survival advantage compared with CCR7-deficient lymphoma cells, which were excluded from this zone. Within the niche, lymphoma cells stimulated a reciprocal cross-talk with gp38+ fibroblastic reticular cells. This reciprocal cooperation program was mediated by lymphoma B cell–presented lymphotoxin, which acted on lymphotoxin-β–receptor-bearing stromal cells followed by alteration of stromal cellular composition. Cross-talk inhibition by lymphotoxin-α deletion and using a lymphotoxin-β receptor-immunoglobulin fusion protein impaired lymphoma growth. Thus, abrogation of CCR7-governed migration and of sustained lymphotoxin signaling could provide new targets in lymphoma therapy.

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In vitro maturation and migration of immature dendritic cells after chemokine receptor 7 transfection

Canadian Journal of Microbiology ◽

10.1139/w09-041 ◽

2009 ◽

Vol 55 (7) ◽

pp. 859-866 ◽

Cited By ~ 14

Author(s):

Hai-ming Xin ◽

Yi-zhi Peng ◽

Zhi-qiang Yuan ◽

Hao Guo

Keyword(s):

Dendritic Cells ◽

Immune Tolerance ◽

Chemokine Receptor ◽

Recombinant Adenovirus ◽

Gene Transfection ◽

Interleukin 10 ◽

Lymphoid Organs ◽

Immature Dendritic Cells ◽

Secondary Lymphoid Organs

Dendritic cells are specialized antigen-presenting cells that regulate immunity and tolerance. Chemokine receptor 7 (CCR7), which is expressed by mature dendritic cells, mediates the migration of the cells to secondary lymphoid organs and thus regulates immune responses. It has been demonstrated that immature dendritic cells can induce immune tolerance, but they do not express CCR7 and cannot migrate to secondary lymphoid organs. We transfected immature dendritic cells with a recombinant adenovirus carrying the CCR7 gene to obtain immature dendritic cells with the ability to migrate. The maturity of the cells was monitored by scanning electron microscopy and flow cytometry. In addition, we assessed the ability of cells to migrate and the function of the cells using in vitro chemotactic and mixed leukocyte reaction assays. The results showed that immature dendritic cells became semi-mature, exhibiting a mild upregulation of co-stimulatory molecular expression and a few dendritic processes. Immunofluorescence assay and Western blotting indicated that CCR7 protein expression increased significantly in immature dendritic cells following CCR7 gene transfection. The in vitro chemotactic assay showed a significantly enhanced ability to migrate in response to CCL19 following CCR7 gene transfection. Moreover, transfected cells showed an enhanced ability to stimulate allogeneic T cell proliferation in vitro, but their ability was significantly weaker than that of mature dendritic cells. Interleukin-10 inhibited the differentiation and maturation of immature dendritic cells. It is concluded that, following CCR7 gene transfection, immature dendritic cells exhibit an enhanced ability to migrate and some of the characteristics of mature cells. Thus, these cells are of potential clinical significance in studies of immune tolerance induction during skin grafting after severe burns.

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Follicular B Helper T Cells Express Cxc Chemokine Receptor 5, Localize to B Cell Follicles, and Support Immunoglobulin Production

Journal of Experimental Medicine ◽

10.1084/jem.192.11.1545 ◽

2000 ◽

Vol 192 (11) ◽

pp. 1545-1552 ◽

Cited By ~ 927

Author(s):

Dagmar Breitfeld ◽

Lars Ohl ◽

Elisabeth Kremmer ◽

Joachim Ellwart ◽

Federica Sallusto ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Chemokine Receptor ◽

Costimulatory Molecule ◽

Lymphoid Organs ◽

Helper T Cells ◽

Cell Homing ◽

Cxc Chemokine ◽

Secondary Lymphoid Organs ◽

Chemokine Receptor 5

Chemokines and their receptors have been identified as major regulators controlling the functional organization of secondary lymphoid organs. Here we show that expression of CXC chemokine receptor 5 (CXCR5), a chemokine receptor required for B cell homing to B cell follicles, defines a novel subpopulation of B helper T cells localizing to follicles. In peripheral blood these cells coexpress CD45RO and the T cell homing CC chemokine receptor 7 (CCR7). In secondary lymphoid organs, CD4+CXCR5+ cells lose expression of CCR7, which allows them to localize to B cell follicles and germinal centers where they express high levels of CD40 ligand (CD40L), a costimulatory molecule required for B cell activation and inducible costimulator (ICOS), a recently identified costimulatory molecule of the CD28 family. Thus, when compared with CD4+CD45RO+CXCR5− cells, CD4+CD45RO+CXCR5+ tonsillar T cells efficiently support the production of immunoglobulin (Ig)A and IgG. In contrast, analysis of the memory response revealed that long-lasting memory cells are found within the CD4+CD45RO+CXCR5− population, suggesting that CXCR5+CD4 cells represent recently activated effector cells. Based on the characteristic localization within secondary lymphoid organs, we suggest to term these cells “follicular B helper T cells” (TFH).

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