Soluble factors
From previous pages, it has become clear that DC activation is essential for mounting an appropriate immune response during infection. We have heard how molecules involved in antigen presentation are increased on the surface of the activated DCs during their maturation. We have also mentioned that during the maturation process DCs change the cytokines that they secrete; these are enormously important for how the DCs interact with the T cells and how the T cells respond. Of the cytokines that DCs produce, IL-10 and IL-12 are particularly important. We will hear more about the effect that cytokines do to the T cells in the next module but in broad terms you can think of IL-12 as a cytokine that tells the T cell to respond, and IL-10 not to respond. The balance and level of these two cytokines is influenced by the environment that the DCs mature in. The DC obtains information from interacting directly with pathogens via PAMPs and also by “listening” to other tissue cells. The ‘advice’ from other cells can come in the form of soluble mediators such as cytokines, lipids, small molecules and danger signals released from damaged cells. All this information is processed by the DCs during its maturation and tweaks the cytokine levels produced by the DC.
So what do these soluble mediators do to our DCs? In resting tissue, the cytokines IL-10 and TGF-β production from local regulatory T cells, macrophages and epithelial cells suppress DC maturation and tell the DC to ‘relax’ and ‘be quiet’. In allergic disease the tissue environment is different due to activation of mast cells that churns out cytokines and small molecules, increased inflammation and increased damage to local tissue. This will make the DC upregulate MHC class II and costimulatory molecules and at the same time reduce the DCs ability to produce IL-12. What do lipids do? Prostaglandin E2 (PGE2) causes DC activation and co-operates with inflammatory cytokines, like IL-6 and TNF-α, in upregulating a chemokines receptor called CCR7 and thereby causing DCs to migrate out of tissues. Perhaps the DC in the lymphatic in the graphic has been through exactly that and is now on its way to the lymph node. PGE2 also increases the DCs IL-10 and reduces the IL-12 production. In contrast to PGE2, histamine has no effect on CCR7 expression. In the presence of LPS or IFN-γ histamine reduces the production of IL-12 and at the same time upregulates the T cell attracting chemokines CCL17 and CCL22. Histamine exposed DCs may therefore instead activate T cells within tissues. So you can see that the DC can take information from its environment in the form of soluble mediators which helps it decide what to do.