Séminaire des équipes de recherche
Logical modeling and model-checking of T-helper cell differentiation and plasticity
- Date : 20/02/2015
- Place : Inria Paris-Rocquencourt - Bâtiment 8
- Guest(s) : Wassim Abou-Jaoude, ENS
T helper (CD4+) lymphocytes play a key role in the regulation of immune responses. Potentially faced with a large diversity of microbial pathogens, antigen-inexperienced (naïve) CD4+ T cells differentiate into various T helper (Th) subsets, which secrete distinct sets of cytokines. This differentiation process requires the integration of multiple signals, mainly produced by antigen presenting cells (APC), triggering specific surface receptors, including the T cell receptor, co-stimulatory molecules, and cytokine receptors.
Diverse combinations of these signals lead to the differentiation of naïve T cells into diverse Th subsets, associated to specific physiopathological functions, tailoring an adaptive response to the invading pathogen. During the last years, experimental studies highlighted the diversity and plasticity of Th lymphocytes, challenging the classical linear view of Th differentiation and raising questions regarding the mechanisms which underlie the observed diversity and plasticity of Th phenotypes. This type of questions can be actually investigated using dynamical modeling.
In particular, logical modeling has proven suitable for the dynamical analysis of large signaling and transcriptional regulatory networks. In this talk, I will present an extended version of a recently published logical model of T-helper cell differentiation, which accounts for novel Th cellular subtypes. Computational methods recently developed to efficiently analyze large models are first used to study static properties of the model (i.e. stables states). Symbolic model checking is then used to analyze reachability properties between Th subtypes upon changes of environmental cues.
The model reproduces novel reported Th subtypes and predicts additional Th hybrid subtypes in term of stables states. Using the model checker NuSMV-ARCTL, an abstract representation of the dynamics is produced providing a global and synthetic view of Th plasticity. The model is consistent with experimental data showing the polarization of naïve Th cells into the canonical Th subtypes, and further predicts substancial plasticity of Th subtypes depending on the signalling environment.