Modeling the mechanisms of action underlying the plasticity of the CD4+ T cell differentiation process

Carbo, A., R. Hontecillas, M. Climent, S. Hoops, P. Lu, K. Wendelsdorf, S. Eubank, M. Marathe, and J. Bassaganya-Riera (2011) Modeling the mechanisms of action underlying the plasticity of the CD4+ T cell differentiation process, AAI Annual Meeting, San Francisco, CA.

Mathematical and computational modeling facilitates concurrent multiparametric analyses of dynamic biological processes. Herein we describe a network model illustrating intracellular pathways controlling a naïve T cell differentiation into Th1, Th2, Th17 or iTreg phenotypes. The model is comprised of 37 differential equations representing 40 reactions and 81 species. The COmplex PAthway SImulator software has been used for model calibration and it shows that our model adequately computes the differentiation of CD4 T cells into the four phenotypes. Moreover, our network includes the nuclear transcription factor peroxisome proliferator activated receptor γ (PPARγ) that modulates the Th17/iTreg plasticity and is highly expressed during IL-4-induced Th2 differentiation. Local model sensitivities demonstrate that PPARγ activation increases the production of FOXP3 when the system is driven into Th17 differentiation. The prediction of this model was validated in vitro using primary mouse CD4+ T cells differentiated into Th17 and treated with 0, 0.25, 0.5, 1, 2, 4, 10 and 40 µM rosiglitazone, a PPARγ agonist. Our differentiation studies confirmed the prediction of our model that increasing concentrations of rosiglitazone in Th1-induced CD4 T cells decrease INFγ and Tbet levels, and increase GATA3 expression in Th2-induced T cells. These data support the prediction of our model regarding the modulation of intracellular networks controlling fate and function of CD4+ T cells by PPARγ