Schulz about her research:
T-helpertype I (Th1) lymphocytes play a central role in the mammalian adaptive immune response against intracellular pathogens. When activated inappropriately, however, they contribute to autoimmune diseases. Although transcription factors and cytokine signals controlling Th1 differentiation have been studied extensively, the exact contribution of each factor remained unclear. It had been known for long that the Th1 master transcription factor T-bet can be induced by the cytokine interferon-g (IFN-g) in an autocrine manner. However, it had remained puzzling, why IFN-g cannot induce Th1 differentiation, which requires another cytokine, interleukin-12 (IL-12). To understand how the various players function together as a regulatory network, a systems biology approach was chosen.

Through close interplay of quantitative experiments and mathematical modelling, the gene-regulatory network governing differentiation of Th1 cells was reconstructed. The Th1 network was found to successively adopt two different states, each controlling a distinct phase of the differentiation process. During an early effect or phase cells fulfill Th1 functions but remain uncommitted, while the following differentiation phase is required for lineage stabilization. The antigenic signal acts as a switch between the two network states since it is required for effect or functions (IFN-g production), but inhibits response to the differentiation signal IL-12. The Th1 master transcription factor T-bet can mediate lineage commitment only during the late differentiation phase. It could be shown that IL-12 drives T-bet differentiation during this differentiation time window, which explains the unique role of IL-12 in Th1 differentiation. Therefore, this network analysis of the dynamic interactions between known key regulators solved a long-standing question regarding the different roles of IFN-g and IL-12 during the Th1 differentiation process.