Quantifying crosstalk among interferon-γ, interleukin-12, and tumor necrosis factor signaling pathways within a TH1 cell model.

T helper (T(H)) cells integrate biochemical cues present in the tissue microenvironment and produce cytokines that orchestrate immune responses. Previous discoveries have revealed a qualitative understanding of how T(H) cells process this biochemical information; however, the lack of methods to quantify how well these depictions apply to a particular cell type limits our ability to translate our knowledge of the immune response from one biological system to another. We used model-based inference methods and quantitative flow cytometric analysis in mouse T(H)1 cells to determine the relative contributions of different putative branches in the signaling network that responds to the cytokine interleukin-12 (IL-12), which links innate and adaptive immunity. The response of T(H)1 cells to IL-12 exhibited hysteresis because it depended on both current and past exposure and engaged a positive feedback mechanism through the direct activation of signal transducer and activator of transcription 1. The hysteresis in the dose-response curve to IL-12 created a transient "memory" by sustaining cytokine secretion after the withdrawal of the stimulus. In summary, this combined experimental and computational approach illustrates how model-based inference can be used to better understand how cells process and act upon biochemical cues present in the tissue microenvironment.