Dendritic cell trafficking: More than just chemokines
Introduction
Dendritic cells (DC) are potent antigen presenting cells with a unique ability in inducing T and B cell responses as well as immune tolerance [1], [2], [3], [4]. DC reside in an immature state in peripheral tissues where they exert a sentinel function for incoming antigens [1], [2], [3], [4]. Upon microbial contact or stimulation by inflammatory cytokines, DC uptake antigens and traffic via the afferent lymphatics into the T cell area of the draining lymph node to initiate immune responses [2], [5], [6], [7]. There is evidence that steady-state migration of DC into the lymph node also occurs in normal conditions and may serve to tolerize T cells against self and non-dangerous antigens [1]. Migration of DC into tissues depends on a cascade of discrete events, including chemokine production and regulation of chemokine receptors [5], [6], [8], [9].
DC are a heterogeneous population that posses unique homing properties [2], [10]. Myeloid blood CD11c+ DC can migrate in response to a wide array of inflammatory chemotactic agonists produced at the peripheral sites of infection and immune reaction [7], [11], [12]. On the other hand, CD123+ plasmacytoid DC are believed to enter lymph nodes across blood high endothelial venules [13]. The expression and regulation of functional chemotactic receptors is likely to be responsible for the different distribution of DC subsets in vivo.
The proper localization of DC to secondary lymphoid organs and their recruitment at sites of inflammation in response to chemotactic stimuli are critical events for optimal immune response [14], [15], [16]. Recent work has documented that a number of chemotactic agonists, different from chemokines, play a relevant role in DC subset recruitment [12], [17], [18], [19], [20]. Furthermore, multiple experimental evidences have shown that chemokine receptor expression is not predictive of DC migration since multiple factors, including prostaglandins, leukotrienes, sphingosine1-phosphate, extracellular nucleotides and some membrane proteins (e.g. CD38) play an important role in the regulation of chemokine receptor function [10], [21], [22], [23], [24]. Therefore, DC migration in vivo is a tightly regulated process controlled at the level, of chemokine production and chemokine receptor expression and function.
Section snippets
Role of chemokines in the recruitment of myeloid dendritic cells
Chemokines are small-secreted chemotactic cytokines that regulate the migration of leukocytes under steady state and inflammatory conditions [8], [25], [26]. Immature DC express a unique repertoire of inflammatory chemokine receptors (e.g. CCR1, CCR2, CCR5, CCR6) [5], [9], [27]. These receptors bind a pattern of “inflammatory” chemokines, including CCL5, CCL2, CCL3, CCL4 and CCL20 (Table 1). In addition, immature DC also express functional CXCR4 [28], the receptor for CXCL12, chemokine that is
Migration of DC to lymphoid organs
A dramatic change in the repertoire of chemokine receptors is promoted by DC activation. This change is responsible for the migration of DC from the periphery to the draining lymph nodes. The signals that promote this process include a variety of maturation factors, such as IL-1, TNF and LPS [39], [40], [41]. Exogenous administration of these molecules promotes the loss of DC from the periphery within a few hours (i.e. 6–10 h); mice treated with neutralizing antibodies to IL-1 or TNF show an
Migration of plasmacytoid dendritic cells
Plasmacytoid DC are a rare subset of cells present in circulation and in secondary lymphoid organs [13], [68]. These cells express MHC class II, have the ability to activate T lymphocytes, and secrete high levels of type I interferon following activation. The production of type I interferon is believed to play a crucial role in anti-viral immune responses and in the activation of other leukocyte populations, like B lymphocytes and NK cells [13], [69].
The expression of chemokine receptors on
Nonchemokine chemotactic factors for dendritic cells
DC express a wide variety of receptors for chemotactic agonists different from chemokines (Fig. 2). These include receptors for bacterial components, bioactive lipids and for signals of “tissue danger”. These chemotactic stimuli are rapidly produced (within minutes) at the site of inflammation and represent an early signal for the recruitment of DC, or their precursors, that can precede chemokines action.
Early work performed by this group documented that myeloid immature DC, but not mature DC,
Regulation of dendritic cell migration
Multiple evidences have shown that chemokine receptor expression is not predictive of DC migration suggesting that the coupling of chemokine receptors to chemotaxis is also regulated at the signaling level [10], [21]. For instance the simultaneous exposure of DC to maturation factors and anti-inflammatory cytokines (i.e. IL-10) uncouples inflammatory chemokine receptors from chemotaxis and converts them in scavenging chemokine receptors [21]. Recent findings revealed that eicosanoids, such as
Dendritic cells as regulators of innate immunity
In addition to the change in the pattern of chemokine receptors, maturation of DC is associated with a complex program of gene transcription [121], [122]. Maturing DC were shown to produce IL-2 that is pivotal for the activation of NK cell response [121]. In addition, TLR-mediated maturation of DC increases the expression of the NADPH oxidase components required for the release of oxygen radicals [123]. Both functions are likely to be important to control the dissemination of pathogens to
Concluding remarks
DC represent a complex system of cells which includes multiple subsets with different biological activity and traveling properties. DC differentiate along multiple pathways and are characterized by different states of maturation, each one associated with peculiar functions and membrane phenotypes. The interaction of chemokines with DC is vital for normal immune function. However, there is a considerable array of molecules that modulate DC migration, and for some of them a complete understanding
Acknowledgements
This work was supported by AIRC (Associazione Italiana per la Ricerca sul Cancro), MIUR (Ministero dell’Istruzione Università e Ricerca), Association for International Cancer Resarch (grant no. 04-223) and by Fondazione Berlucchi.
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