A model for the integration of conflicting exogenous and endogenous signals by dendritic cells

Abstract

Cells of the immune system are confronted with opposing pro- and anti-inflammatory signals. Dendritic cells (DC) integrate these cues to make informed decisions whether to initiate an immune response. Confronted with exogenous microbial stimuli, DC endogenously produce both anti- (IL-10) and pro-inflammatory (TNF$\alpha$) cues whose joint integration controls the cell's final decision. We combine experimental measurements with theoretical modeling to quantitatively describe the integration mode of these opposing signals. We propose a two step integration model that modulates the effect of the two types of signals: an initial bottleneck integrates both signals (IL-10 and TNF$\alpha$), the output of which is later modulated by the anti-inflammatory signal. We show that the anti-inflammatory IL-10 signaling is long ranged, as opposed to the short-ranged pro-inflammatory TNF$\alpha$ signaling. The model suggests that the population averaging and modulation of the pro-inflammatory response by the anti-inflammatory signal is a safety guard against excessive immune responses.