Tuning the volume of the immune response: strength and persistence of stimulation determine migration and cytokine secretion of dendritic cells

Abstract

Migration to lymph nodes and secretion of cytokines are critical functions of mature dendritic cells (DCs); however, these 2 functions are not necessarily linked. This is the first report showing that quantitative differences in identical signaling pathways determine DC migration and cytokine secretion. Using different polymerized forms of CD40 ligand, we demonstrate that the strength and persistence of CD40 signaling can induce either function. Induction of monocyte-derived DC (MoDC) migration required a weak and transient CD40 signal, whereas strong and persistent CD40 signaling blocked migration and biased toward cytokine secretion. In contrast to MoDCs, CD40 activation of CD1c ؉ peripheral blood DCs (PBDCs) induced a nonpersistent, intracellular signaling profile resulting in migratory-type DCs unable to secrete interleukin-12p70 (IL-12p70). Extracellular signal-regulated kinase 1/2 (ERK1/2) and p38K activation synergistically mediated cytokine secretion, whereas migration was enhanced by p38K activation but reduced by persistent ERK1/2 activity. This model of signal strength and persistence also applied when stimulating DCs with intact microbes. Thus, a novel concept emerges in which the type of immune response induced by DCs is tuned by the strength and persistence of DC activating signals.

Prostaglandin I2 Analogs Inhibit Proinflammatory Cytokine Production and T Cell Stimulatory Function of Dendritic Cells

“…Similar to the effect of PGI 2 analogs, PGE 2 has been shown to inhibit IL-12, TNF-␣, and IL-6 production by BMDCs, suppress MHC class II expression, and enhance IL-10 production (22,29,38,39). Studies showed that DCs may be activated to produce high levels of proinflammatory cytokines and remain at sites of inflammation or develop into CCR7-expressing cells that allow them to migrate to the draining lymph nodes and induce Ag-specific immune responses (50,51). These migratory DCs produce low levels of inflammatory cytokines (50).…”

“…Studies showed that DCs may be activated to produce high levels of proinflammatory cytokines and remain at sites of inflammation or develop into CCR7-expressing cells that allow them to migrate to the draining lymph nodes and induce Ag-specific immune responses (50,51). These migratory DCs produce low levels of inflammatory cytokines (50). PGE 2 promotes the generation of the migratory DCs, inhibits proinflammatory cytokine production (50), and up-regulates CCR7 expression (52,53).…”

“…These migratory DCs produce low levels of inflammatory cytokines (50). PGE 2 promotes the generation of the migratory DCs, inhibits proinflammatory cytokine production (50), and up-regulates CCR7 expression (52,53). For generation of migrating DCs, PGE 2 is required at early time points of DC maturation (53).…”

“…Because of the instability of PGI 2 , the physiologic concentration of PGI 2 in the site of inflammation is difficult to determine. However, considering that iloprost exhibited an equilibrium dissociation constant for the IP with a K d value of 9.8 nM (62), and PGI 2 stimulated adenylyl cyclase activity with an EC 50 (the concentration that leads to 50% maximal response) at 6.6 nM in NCB-20 cells (63), it may be reasonable to estimate physiologically functional levels of PGI 2 in a range of 10 -100 nM. Therefore, our in vitro data showing the effect of iloprost and cicaprost at a range of 4 -400 nM on cytokine expression, cAMP production, and T cell stimulatory function of DCs appear to have a physiological relevance.…”

Cholera toxin promotes the generation of semi-mature porcine monocyte-derived dendritic cells that are unable to stimulate T cells

“…Activation of MAP kinases and other signal transduction pathways are important upstream events for the induction of DC maturation, migration or cytokine secretion [1,30]. Analysis of key intracellular signalling molecules in Ctx-stimulated MoDC revealed ERK1/2-activation, but no regulation of JNK or NFκB activity.…”