Interplay of phosphorylation kinetics and methylation dynamics leads to complex behavior of Foxp3 and PTEN in computational model of T cell differentiation (IRM6P.709)

Abstract

Abstract We have recently published a mathematical model that demonstrates that differential activation of signaling pathways downstream of TCR by high and low concentrations of antigen can be modeled by varying the duration of antigen stimulation, which results in a mixed population of regulatory (Treg), helper (Th) and inactive cells, a prediction we confirmed experimentally. Analysis of the dynamics of this scenario demonstrated an important role for a feedback loop involving Foxp3, PTEN, and Akt-mTOR signaling, which affects the timing of transient Foxp3 expression and PTEN activity, and the ratio of different phenotypes in the mixed population. We hypothesized that the correlation in the dynamics of Foxp3 and PTEN, which we previously modeled as a direct link between Foxp3 and PTEN, stems from the regulation of both Foxp3 and PTEN expression by the transcription factor Foxo1. We updated the model to test this hypothesis, and preliminary results suggest that the interplay of rapid modulation of Foxo1 activity by Akt with the slower kinetics of methylation/demethylation at the Foxp3 promoter mediated by mTOR can produce dramatic changes in the resulting distribution of phenotypes when the timing of these events is varied. To calibrate this timing in the model, we are currently conducting experiments that will help us determine the time scale for Foxo1 inactivation by Akt and for the effect of Foxo1 on Foxp3 and PTEN expression.