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Differential migration behavior and chemokine production by myeloid and plasmacytoid dendritic cells
Giuseppe Penna1, Marisa Vulcano, Silvano Sozzani
1BioXell, Milan, Italy.
Insights
Myeloid dendritic cells (M-DCs) and plasmacytoid dendritic cells (P-DCs) exhibit distinct migration patterns and chemokine production. P-DCs preferentially migrate to lymphoid organs, while M-DCs recruit specific T-helper cells to inflammation sites.
Area of Science:
- Immunology
- Cell Biology
- Dendritic Cell Biology
Background:
- Dendritic cell (DC) subsets are known, but their trafficking properties remain poorly understood.
- Myeloid dendritic cells (M-DCs) and plasmacytoid dendritic cells (P-DCs) are distinct subsets with potentially different functions.
Purpose of the Study:
- To investigate and compare the migratory capacities and chemokine production profiles of human M-DCs and P-DCs.
- To elucidate the functional roles of chemokine receptors on circulating and mature DC subsets.
Main Methods:
- Isolation of human M-DCs and P-DCs from blood.
- Analysis of chemokine receptor expression (CCR5, CCR7, CXCR3) ex vivo.
- Assessment of chemokine receptor function following maturation induced by CD40 ligation.
- Measurement of chemokine production (CCL17, CCL22, CCL3) by DC subsets.
Main Results:
- M-DCs and P-DCs show differential migration capacities.
- P-DCs express higher levels of CCR5, CCR7, and CXCR3, but these receptors are largely non-functional in circulating cells.
- Maturation upregulates CCR7-mediated migration in P-DCs, while downregulating inflammatory chemokine receptors.
- M-DCs produce high levels of CCL17/TARC and CCL22/MDC, recruiting T-helper 2 and regulatory T cells.
- P-DCs predominantly produce CCL3/MIP-1alpha, a pro-inflammatory chemokine.
Conclusions:
- M-DCs and P-DCs possess distinct migratory behaviors and chemokine production profiles.
- P-DCs are primed for migration to secondary lymphoid organs, while M-DCs are geared towards recruiting specific T-cell subsets to inflammation sites.
- These differences highlight the specialized roles of DC subsets in orchestrating immune responses.
Abstract:
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.