DCs that migrate from tissues to lymph nodes have a life expectancy of only a few days and can therefore be viewed as disposable packets, each carrying a given amount of peptide–MHC complexes, costimulatory molecules and cytokines. These packets are assembled during DC maturation, a process that is initiated by pathogens and/or inflammatory stimuli. The production of homogeneous populations of human immature DCs from human peripheral blood monocytes cultured with granulocyte/macrophage-colony-stimulating factor and IL-4 [11
] has been instrumental in identifying the maturation stimuli and in dissecting the DC maturation process (Fig. ).
Figure 2 The maturation programme studied in monocyte-derived dendritic cells. DC, dendritic cells; ELC, endothelial-like cells; FcR, receptors for crystallizable fragment [of antibody]; GM-CSF, granulocyte/macrophage-colony-stimulating factor; ICAM-1, intracellular (more ...)
DC maturation is triggered and modulated by a variety of receptors for microbial products, cytokines and T cells [12
]. Human monocyte derived and myeloid DCs express several Toll-like receptors such as TLR2 and TLR4 that trigger maturation in response to bacterial peptidoglycan and lipopolysaccharide, respectively. Interestingly, these receptors are absent in plasmacytoid DCs (also known as interferon-producing cells [IPC]) that instead express TLR9, which mediates the response to CpG DNA [14
]. The differential responsiveness of myeloid and plasmacytoid DCs to pathogens underlines a division of labour between human DC subsets. DC maturation can be also triggered by tumour necrosis factor (TNF)-α and IL-1, and can be inhibited by IL-10. Finally, all DC types are exquisitely sensitive to T-cell feedback signals delivered by activated T cells through CD40 ligand (CD40L).
The maturation process coordinately regulates antigen capturing, processing and presentation, expression of costimulatory molecules, cytokine production and lifespan. Immature DCs are extremely efficient in antigen capture since they possess high levels of constitutive macropinocytosis and express endocytic receptors for microbial patterns, such as the mannose receptor [16
]. Maturation increases synthesis of MHC class II molecules, while decreasing their degradation, thus favouring the rapid accumulation of long-lived peptide–MHC complexes, which are retained for several days, while class II synthesis is shut off [17
]. Presentation on MHC class I molecules is also enhanced by an approximately 10-fold increase in the rate of synthesis, which is sustained in mature DCs [18
]. DCs are capable of transporting phagocytosed antigens from the endocytic compartment to the cytosol, leading to their 'cross-presentation' to CD8+
T cells [19
]. Finally, maturation stimuli upregulate the expression of B7.1 and B7.2, thus enhancing the T-cell stimulatory capacity of DCs. While the upregulation of MHC molecules ensures higher capacity for antigen presentation, upregulation of costimulatory molecules ensures an efficient amplification of signalling in naïve T cells.
Cytokine production by DCs is subject to a tight regulation, which is particularly relevant in the case of IL-12 and IFN-I, the major Th1-polarizing cytokines [21
]. IL-12 production is elicited by most pathogens and is boosted by activated T cells through CD40L [22
]. In contrast, IL-12 is not induced by other maturation stimuli such as TNF-α, IL-1, and cholera toxin. IL-12 production can be modulated by cytokines and mediators present during induction of maturation: IFN-γ and IL-4 enhance IL-12 production induced by appropriate stimuli, while prostaglandin E2
and IL-10 exert an inhibitory effect. In addition, one has to consider that IL-12 production is restricted to a narrow temporal window, 8–16 hours after induction of DC maturation [9
]. In summary, the Th1-polarizing capacity of DCs is contingent on a number of variables that include the lineage of DCs, the microenvironment in which they are stimulated, the maturation stimuli, and the kinetics of maturation (Fig. ).
Figure 3 Reactivity, flexibility, kinetics and exhaustion in myeloid and plasmacytoid dendritic cells (DCs). The figure summarizes the properties of immature myeloid and plasmacytoid DCs. Indicated are the most relevant Toll-like receptors (TLR) and chemokine (more ...)