Sequential involvement of CCR2 and CCR6 ligands for immature dendritic cell recruitment: possible role at inflamed epithelial surfaces (original) (raw)
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International Immunology, 1999
Dendritic cells (DC) are highly motile antigen-presenting cells that are recruited to sites of infection and inflammation to antigen uptake and processing. Then, to initiate T cell-dependent immune responses, they migrate from non-lymphoid organs to lymph nodes and the spleen. Since chemokines have been involved in human DC recruitment, we investigated the role of chemokines on mouse DC migration using the mouse growth factor-dependent immature DC line (D1). In this study, we characterized receptor expression, responsiveness to chemoattractants and chemokine expression of D1 cells during the maturation process induced by lipopolysaccharide (LPS). MIP-1α and MIP-5 were found to be the most effective chemoattractants, CCR1 was the main receptor expressed and modulated during LPS treatment, and MIP-2, RANTES, IP-10 and MCP-1 were the chemokines modulated during DC maturation. Thus, murine DC respond to a unique set of CC and CXC chemokines, and the maturational stage determines the program of chemokine receptors and chemokines that are expressed. Since CCR1 is modulated during the early phases of DC maturation, our results indicate that the CCR1 receptor may participate in the recruitment and maintenance of DC at the inflammatory site.
2010
DCs (dendritic cells) function as sentinels of the immune system. They traffic from the blood to the tissues where, while immature, they capture antigens. They then leave the tissues and move to the draining lymphoid organs where, converted into mature DC, they prime naive T cells. This suggestive link between DC traffic pattern and functions led us to investigate the chemokine responsiveness of DCs during their development and maturation. DCs were differentiated either from CD34 ϩ hematopoietic progenitor cells (HPCs) cultured with granulocyte/macrophage colony-stimulating factor (GM-CSF) plus tumor necrosis factor (TNF)-␣ or from monocytes cultured with GM-CSF plus interleukin 4. Immature DCs derived from CD34 ϩ HPCs migrate most vigorously in response to macrophage inflammatory protein (MIP)-3 ␣ , but also to MIP-1 ␣ and RANTES (regulated on activation, normal T cell expressed and secreted). Upon maturation, induced by either TNF-␣ , lipopolysaccharide, or CD40L, DCs lose their response to these three chemokines when they acquire a sustained responsiveness to a single other chemokine, MIP-3  . CC chemokine receptor (CCR)6 and CCR7 are the only known receptors for MIP-3 ␣ and MIP-3  , respectively. The observation that CCR6 mRNA expression decreases progressively as DCs mature, whereas CCR7 mRNA expression is sharply upregulated, provides a likely explanation for the changes in chemokine responsiveness. Similarly, MIP-3  responsiveness and CCR7 expression are induced upon maturation of monocytederived DCs. Furthermore, the chemotactic response to MIP-3  is also acquired by CD11c ϩ DCs isolated from blood after spontaneous maturation. Finally, detection by in situ hybridization of MIP-3 ␣ mRNA only within inflamed epithelial crypts of tonsils, and of MIP-3  mRNA specifically in T cell-rich areas, suggests a role for MIP-3 ␣ /CCR6 in recruitment of immature DCs at site of injury and for MIP-3  /CCR7 in accumulation of antigen-loaded mature DCs in T cell-rich areas.
Journal of Experimental Medicine, 1997
Dendritic cells initiate immune responses by ferrying antigen from the tissues to the lymphoid organs for presentation to lymphocytes. Little is known about the molecular mechanisms underlying this migratory behavior. We have identified a chemokine receptor which appears to be selectively expressed in human dendritic cells derived from CD34+ cord blood precursors, but not in dendritic cells derived from peripheral blood monocytes. When stably expressed as a recombinant protein in a variety of host cell backgrounds, the receptor shows a strong interaction with only one chemokine among 25 tested: the recently reported CC chemokine macrophage inflammatory protein 3α. Thus, we have designated this receptor as the CC chemokine receptor 6. The cloning and characterization of a dendritic cell CC chemokine receptor suggests a role for chemokines in the control of the migration of dendritic cells and the regulation of dendritic cell function in immunity and infection.
Dendritic cells (DCs) form a network comprising different populations that initiate and differentially regulate immune responses. Langerhans cells (LCs) represent a unique population of DCs colonizing epithelium, and we present here observations suggesting that macrophage inflammatory protein (MIP)-3 ␣ plays a central role in LC precursor recruitment into the epithelium during inflammation. (a) Among DC populations, MIP-3 ␣ was the most potent chemokine inducing the selective migration of in vitro-generated CD34 ϩ hematopoietic progenitor cell-derived LC precursors and skin LCs in accordance with the restricted MIP-3 ␣ receptor (CC chemokine receptor 6) expression to these cells. (b) MIP-3 ␣ was mainly produced by epithelial cells, and the migration of LC precursors induced by the supernatant of activated skin keratinocytes was completely blocked with an antibody against MIP-3 ␣ . (c) In vivo, MIP-3 ␣ was selectively produced at sites of inflammation as illustrated in tonsils and lesional psoriatic skin where MIP-3 ␣ upregulation appeared associated with an increase in LC turnover. (d) Finally, the secretion of MIP-3 ␣ was strongly upregulated by cells of epithelial origin after inflammatory stimuli (interleukin 1  plus tumor necrosis factor ␣ ) or T cell signals. Results of this study suggest a major role of MIP-3 ␣ in epithelial colonization by LCs under inflammatory conditions and immune disorders, and might open new ways to control epithelial immunity.
Down-regulation of the β-chemokine receptor CCR6 in dendritic cells mediated by TNF-α and IL-4
Journal of Leukocyte Biology, 1999
Chemokines are involved in the control of dendritic cell (DC) trafficking, which is critical for the immune response. We have generated DC from human umbilical cord blood CD34 ؉ progenitors cultured with granulocyte-macrophage colonystimulating factor, tumor necrosis factor ␣ (TNF-␣), and stem cell factor. Using an anti-CCR6 monoclonal antibody, we observed that these cells showed maximum expression of this -chemokine receptor when they were immature, as determined by their relatively low expression of several DC maturation markers such as CD1a, CD11c, CD14, CD40, CD80, and CD83. Immature DC responded strongly to macrophage inflammatory protein-3␣ (MIP-3␣), the CCR6 ligand, in migration and calcium mobilization assays. CCR6 expression decreased in parallel with the DC maturation induced by prolonged TNF-␣ treatments. Interleukin-4 was also able to decrease CCR6 protein levels. Our findings suggest that the MIP-3␣/CCR6 interaction plays an important role in the trafficking of immature DC to chemokine production sites such as injured or inflamed peripheral tissues, where DC undergo maturation on contact with antigens.
Blood, 1999
We examined the potential involvement of two CC chemokine receptors (CCRs), CCR-1 and CCR-3, in the functional activation of granulocyte-macrophage colony-stimulating factor (GM-CSF) plus interleukin-4 (IL-4)-generated human peripheral blood monocyte-derived immature dendritic cells (DCs). Flow cytometric analysis showed that CCR-1, CCR-3, CCR-5, and CXC chemokine receptor (CXCR)-4 were expressed on the cell surface of monocyte-derived DCs. Treatment with a monoclonal antibody (MoAb) to either CCR-1 or CCR-3 but not MoAbs to CCR-5 and CXCR-4 abolished chemotactic migration of monocyte-derived DCs. The DCs treated with either the anti-CCR-1 MoAb or anti-CCR-3 MoAb were less efficient than untreated DCs in proliferation of allogeneic T cells (TCs) and TC-derived secretion of interferon-gamma (IFN-gamma). The homotypic aggregation of DCs and heterotypic aggregation of DCs with TCs were suppressed by the anti-CCR-1 MoAb or anti-CCR-3 MoAb. These results indicate that CCR-1 and CCR-3 spe...
Journal of Experimental Medicine, 2000
Dendritic cells (DCs) form a network comprising different populations that initiate and differentially regulate immune responses. Langerhans cells (LCs) represent a unique population of DCs colonizing epithelium, and we present here observations suggesting that macrophage inflammatory protein (MIP)-3 ␣ plays a central role in LC precursor recruitment into the epithelium during inflammation. (a) Among DC populations, MIP-3 ␣ was the most potent chemokine inducing the selective migration of in vitro-generated CD34 ϩ hematopoietic progenitor cell-derived LC precursors and skin LCs in accordance with the restricted MIP-3 ␣ receptor (CC chemokine receptor 6) expression to these cells. (b) MIP-3 ␣ was mainly produced by epithelial cells, and the migration of LC precursors induced by the supernatant of activated skin keratinocytes was completely blocked with an antibody against MIP-3 ␣ . (c) In vivo, MIP-3 ␣ was selectively produced at sites of inflammation as illustrated in tonsils and lesional psoriatic skin where MIP-3 ␣ upregulation appeared associated with an increase in LC turnover. (d) Finally, the secretion of MIP-3 ␣ was strongly upregulated by cells of epithelial origin after inflammatory stimuli (interleukin 1  plus tumor necrosis factor ␣ ) or T cell signals. Results of this study suggest a major role of MIP-3 ␣ in epithelial colonization by LCs under inflammatory conditions and immune disorders, and might open new ways to control epithelial immunity.
Differential migration behavior and chemokine production by myeloid and plasmacytoid dendritic cells
Human Immunology, 2002
The existence of dendritic cell (DC) subsets is firmly established, but their trafficking properties are still largely unknown. We have indicated that myeloid dendritic cells (M-DCs) and plasmacytoid dendritic cells (P-DCs) isolated from human blood differ widely in the capacity to migrate to chemotactic stimuli. The pattern of chemokine receptors expressed ex vivo by both subsets is similar, but P-DCs display, compared with M-DCs, higher levels of CC chemokine receptor (CCR)5, CCR7, and CXCR3. Intriguingly, most chemokine receptors of P-DCs, in particular those specific for inflammatory chemokines and classical chemotactic agonists, are not functional in circulating cells. Following maturation induced by cluster designation (CD)40 ligation, the receptors for inflammatory chemokines are downregulated and CCR7 on P-DCs becomes coupled to migration. The drastically impaired capacity of blood P-DCs to migrate in response to inflammatory chemotactic signals contrasts with the response to lymph node-homing chemokines, indicating a propensity to migrate to secondary lymphoid organs rather than to sites of inflammation. The distinct migration behavior of DC subsets is accompanied by a different profile of chemokine production. In contrast to the high production by M-DCs, the homeostatic CC chemokine ligand (CCL)17/ thymus- and activation-regulated chemokine (TARC) is not produced by PDCs in response to any stimulus tested and their production of CCL22/MDC is minimal, if any, compared with M-DCs. Thus, stimulated M-DCs, but not P-DCs, are able to produce high levels of chemokines recruiting T-helper 2 cells (Th2) and T-regulatory cells. Conversely, the proinflammatory chemokine CCL3/macrophage inflammatory protein (MIP)-1alpha is predominantly produced by P-DCs. Therefore, P-DCs appear to produce preferentially proinflammatory chemokines, but to respond selectively to homeostatic ones, whereas the reverse is true for M-DCs, highlighting not only the different migratory properties of these DC subsets, but also their capacity to recruit different cell types at inflammation sites.