Inferring relevant control mechanisms for interleukin-12 signaling in naïve CD4+ T cells.

Interleukin-12 (IL-12) is a key cytokine involved in shaping the cell-mediated immunity to intracellular pathogens. IL-12 initiates a cellular response through the IL-12 signaling pathway, a member of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) family of signaling networks. The JAK/STAT pathway includes several regulatory elements; however, the dynamics of these mechanisms are not fully understood. Therefore, the objective of this study was to infer the relative importance of regulatory mechanisms that modulate the activation of STAT4 in naïve CD4(+) T cells. Dynamic changes in protein expression and activity were measured using flow cytometry and these data were used to calibrate a mathematical model of IL-12 signaling. An empirical Bayesian approach was used to infer the relative strengths of the different regulatory mechanisms in the system. The model predicted that IL-12 receptor expression is regulated by a dynamic, autonomous program that was independent of STAT4 activation. In summary, a mathematical model of the canonical IL-12 signaling pathway used in conjunction with a Bayesian framework provided high-confidence predictions of the system-specific control mechanisms from the available experimental observations.