From the two-dimensional Th1 and Th2 phenotypes to high-dimensional models for gene regulation

The T(h)1/T(h)2 paradigm has been used for decades to characterize phenotypically different immune responses. Recent discoveries, e.g. T(h)17 cells are adding more dimensions to the helper T cell framework, and the T(h)1/T(h)2 paradigm is currently being extended to include these new phenotypes. Previous mathematical models cannot easily be extended to accommodate these new phenotypes, and therefore these discoveries call for a new type of models. We devised a new model of helper T cell differentiation that describes expression of, and interactions between, the master regulators determining the phenotypic polarization of helper T cells. The model is able to describe any number of master regulators and is grounded on transcription factors binding promoter sites and binding each other. The model allows for stable switches between several different phenotypes. Furthermore, the model accounts for the kinetics of FoxP3 and GATA3 mRNA expression measured after stimulating naive helper (CD4+CD45RA+) T cells under various circumstances. Due to its n-dimensional character, this model may easily be applied to other developmental processes that involve master regulators.