Vassili Soumelis | bioRxiv Science

bioRxiv2016

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

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) 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), 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 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.

Immunology↗

bioRxiv2014

Model checking to assess T-helper cell plasticity

Computational modeling constitutes a crucial step towards the functional understanding of complex cellular networks. In particular, logical modeling has proven suitable for the dynamical analysis of large signaling and transcriptional regulatory networks. In this context, signaling input components are generally meant to convey external stimuli, or environmental cues. In response to such external signals, cells acquire specific gene expression patterns modeled in terms of attractors (e.g. stable states). The capacity for cells to alter or reprogram their differentiated states upon changes in environmental conditions is referred to as cell plasticity.\n\nIn this article, we present a multivalued logical framework along with computational methods recently developed to efficiently analyze large models. We mainly focus on a symbolic model checking approach to investigate switches between attractors subsequent to changes of input conditions.\n\nAs a case study, we consider the cellular network regulating the differentiation of T-helper cells, which orchestrate many physiological and pathological immune responses. To account for novel cellular subtypes, we present an extended version of a published model of T-helper cell differentiation. We then use symbolic model checking to analyze reachability properties between T-helper subtypes upon changes of environmental cues. This allows for the construction of a synthetic view of T-helper cell plasticity in terms of a graph connecting subtypes with arcs labeled by input conditions. Finally, we explore novel strategies enabling specific T-helper cell polarizing or reprograming events.

Systems Biology↗