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

TL;DR

This paper presents a combined experimental and theoretical study of how dendritic cells integrate conflicting pro- and anti-inflammatory signals, revealing a two-step model with long-range IL-10 and short-range TNFα signaling to prevent excessive immune responses.

Contribution

It introduces a novel two-step integration model for dendritic cell signaling, combining experimental data with theoretical analysis to explain immune response regulation.

Findings

IL-10 signaling is long-ranged, unlike short-ranged TNFα signaling.

The integration process involves an initial bottleneck that combines signals, followed by modulation.

Population averaging and modulation serve as safety guards against excessive responses.

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.