A Mathematical Model for the Reciprocal Differentiation of T Helper 17 Cells and Induced Regulatory T Cells

The reciprocal differentiation of T helper 17 (TH17) cells and induced regulatory T (iTreg) cells plays a critical role in both the pathogenesis and resolution of diverse human inflammatory diseases. Although initial studies suggested a stable commitment to either the TH17 or the iTreg lineage, recent results reveal remarkable plasticity and heterogeneity, reflected in the capacity of differentiated effectors cells to be reprogrammed among TH17 and iTreg lineages and the intriguing phenomenon that a group of naïve precursor CD4+ T cells can be programmed into phenotypically diverse populations by the same differentiation signal, transforming growth factor beta. To reconcile these observations, we have built a mathematical model of TH17/iTreg differentiation that exhibits four different stable steady states, governed by pitchfork bifurcations with certain degrees of broken symmetry. According to the model, a group of precursor cells with some small cell-to-cell variability can differentiate into phenotypically distinct subsets of cells, which exhibit distinct levels of the master transcription-factor regulators for the two T cell lineages. A dynamical control system with these properties is flexible enough to be steered down alternative pathways by polarizing signals, such as interleukin-6 and retinoic acid and it may be used by the immune system to generate functionally distinct effector cells in desired fractions in response to a range of differentiation signals. Additionally, the model suggests a quantitative explanation for the phenotype with high expression levels of both master regulators. This phenotype corresponds to a re-stabilized co-expressing state, appearing at a late stage of differentiation, rather than a bipotent precursor state observed under some other circumstances. Our simulations reconcile most published experimental observations and predict novel differentiation states as well as transitions among different phenotypes that have not yet been observed experimentally. Author Summary: In order to perform complex functions upon pathogenic challenges, the immune system needs to efficiently deploy a repertoire of specialized cells by inducing the differentiation of precursor cells into effector cells. In a critical process of the adaptive immune system, one common type of precursor cell can give rise to both T helper 17 cells and regulatory T cells, which have distinct phenotypes and functions. Recent discoveries have revealed a certain heterogeneity in this reciprocal differentiation system. In particular, treating precursor cells with a single differentiation signal can result in a remarkably diverse population. An understanding of such variable responses is limited by a lack of quantitative models. Our mathematical model of this cell differentiation system reveals how the control system generates phenotypic diversity and how its final state can be regulated by various signals. The model suggests a new quantitative explanation for the scenario in which the master regulators of two different T cell lineages can be highly expressed in a single cell. The model provides a new framework for understanding the dynamic properties of this type of regulatory network and the mechanisms that help to maintain a balance of effector cells during the inflammatory response to infection.