Functional organization of secondary lymphoid organs by homeostatic chemokines.
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Biomedical subjects
A Schubel
Publications and source records attributed to A Schubel.
CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs.
The proper function of immune surveillance requires well-coordinated mechanisms in order to guide the patrolling immune cells through peripheral tissues and into secondary lymphoid organs. Analyzing gene-targeted mice, we identified the chemokine receptor CCR7 as an important organizer of the primary immune response. CCR7-deficient mice show severely delayed kinetics regarding the antibody response and lack contact sensitivity and delayed type hypersensitivity reactions. Due to the impaired migration of lymphocytes, these animals reveal profound morphological alterations in all secondary lymphoid organs. Upon activation, mature skin dendritic cells fail to migrate into the draining lymph nodes. Thus, in order to bring together lymphocytes and dendritic cells to form the characteristic microarchitecture of secondary lymphoid organs, CCR7 is required to rapidly initiate an adoptive immune response.
Animals↗
The murine chemokine receptor CXCR4 is tightly regulated during T cell development and activation.
We have characterized the murine homolog of the HIV-co-receptor CXCR4 during T cell development and activation. Our data demonstrate that this chemokine receptor, although highly conserved between human and mouse, is differently expressed and regulated in both species. Mitogenic activation resulted in an increase of surface CXCR4 on murine T cells within 2 days, whereas the receptor was strongly down-regulated on human T cells during this period. Furthermore, intraperitoneal immunization of mice resulted in a strong increase of splenic and mesenteric cytotoxic T cells co-expressing CXCR4. It is interesting that, on thymocytes, expression of CXCR4 is restricted to CD4+CD8+ cells. Stromal cell-derived factor-1alpha, a natural ligand of CXCR4, induced chemotaxis of thymocytes and was found to counteract dexamethasone-induced apoptosis to a certain extent in these cells. Thus, our data show that expression of CXCR4 is tightly controlled on murine T cells and indicate that this highly conserved chemokine receptor might serve different functions in humans and mice.
Animals↗
Intracellular and surface expression of the HIV-1 coreceptor CXCR4/fusin on various leukocyte subsets: rapid internalization and recycling upon activation.
We describe the expression and regulation of the HIV-1 coreceptor CXCR4/fusin. Using anti-CXCR4 mAb, we demonstrate that this chemokine receptor is highly expressed on neutrophils, monocytes, B cells, and naive T cells among peripheral blood cells. In secondary lymphoid organs CXCR4 was found to be expressed on B cells. However, individual variations with regard to surface expression could be observed on T cells. Expression of the receptor is not confined to the cell surface, as large amounts of intracellular stores can be found on various leukocytes. Upon activation with phorbol esters the amount of cell surface-expressed CXCR4 on lymphocytes increases twofold within 30 s before it is completely down-regulated within the next 2 min. Incubation of leukocytes with stroma derived factor-1alpha, the natural ligand for CXCR4, induces down-regulation of up to 60% of surface-expressed receptors in a pertussis toxin-insensitive manner. Interestingly, receptor cross-linking caused by incubation of cells with anti-CXCR4 mAb triggers receptor trafficking, in that the receptor is rapidly internalized and recycled to the cell surface. Therefore, receptor internalization and recycling may regulate the functional interaction of the receptor with envelope proteins during an initial step of HIV-1 infection.
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