Quantifying Cross-Talk Among Interferon-γ, Interleukin-12 and Tumor Necrosis Factor Signaling Pathways within a TH1 Cell Model: A Model-Based Inference Approach

T helper cells integrate biochemical cues present within the tissue microenvironment to orchestrate immunity via production of cytokines. Prior discoveries reveal a qualitative understanding of how T helper cells process this biochemical information, as frequently depicted as signaling cartoons. However, the lack of methods for quantifying how well these signaling cartoons apply to a particular cell type presents a major hurdle for translating our knowledge of immunity across systems. The objective of this study was to illustrate how model-based inference methods, in conjunction with quantitative cytometry-based methods, can be used to reason about the relative contributions of different putative branches within a signaling network. A cellular model of mouse T_H1 cells was used to quantify the functional response to Interleukin-12 (IL-12), a key cytokine that links innate to adaptive immunity. Our results demonstrate that the response of T helper cells to IL-12, as modeled by a mouse IL-12-dependent T_H1 cell line, is a dynamic nonlinear process that reflects a hysteresis in response and engages a positive feedback mechanism via direct activation of STAT1. The hysteresis in the dose-response curve to IL-12 creates a transient "memory" by sustaining cytokine secretion following the withdraw of the stimuli. In summary, this combined experimental and computational approach illustrates how model-based inference can be used to obtain greater fidelity in understanding how cells process and act upon biochemical cues present within the tissue microenvironment.