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

Migration to lymph nodes and secretion of cytokines are critical functions of ma-ture dendritic cells (DCs); however, these 2 functions are not necessarily linked. This is the first report showing that quan-titative differences in identical signaling pathways determine DC migration and cytokine secretion. Using different poly-merized forms of CD40 ligand, we demon-strate that the strength and persistence of CD40 signaling can induce either func-tion. 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 se-cretion. In contrast to MoDCs, CD40 acti-vation of CD1c peripheral blood DCs (PBDCs) induced a nonpersistent, intra-cellular signaling profile resulting in mi-gratory-type DCs unable to secrete inter-leukin-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 persis-tence also applied when stimulating DCs with intact microbes. Thus, a novel con-cept emerges in which the type of im-mune response induced by DCs is tuned by the strength and persistence of DC activating signals. (Blood. 2004;104