The competitive nature of STAT complex formation drives phenotype switching of T cells

Signal transducers and activators of transcription (STATs) are key molecular determinants of T cell fate and effector function. A number of inflammatory diseases are characterized by an altered balance of T cell phenotypes and cytokine secretion. STATs, therefore, represent viable therapeutic targets in numerous pathologies. However, the underlying mechanisms of how the same STAT proteins regulate both the development of different T cell phenotypes and their plasticity during changes in extracellular conditions remain unclear. In this study, we investigated the STAT mediated regulation of T cell phenotype formation and plasticity using mathematical modeling and experimental data for intracellular STAT signaling proteins. The close fit of our model predictions to the experimental data allows us to propose a potential mechanism for T cell switching. According to this mechanism, T cell phenotype switching is due to the relative redistribution of STAT dimer complexes caused by the extracellular cytokine-dependent STAT competition effects. The developed model predicts that the balance between the intracellular STAT species defines the amount of the produced cytokines and thereby T cell phenotypes. The model predictions are consistent with the experimentally observed IFN-γ to IL-10 switching that regulates human Th1/Tr1 responses. The proposed model is applicable to a number of STAT signaling circuits. Author Summary The immune system is a highly sophisticated and regulated complex of molecular interactions, the main function of which is to protect the host organism. Despite much recent progress in experimental studies, the underlying 3 molecular mechanisms of autoimmune diseases are still not clear and therefore new approaches to solve this problem are required. Systems biology can offer the necessary analytic tools for deeper elucidation of molecular mechanisms using available experimental data. In this work, we studied T cell plasticity and cytokine production focusing on STAT proteins, one of the key molecular elements of signal transduction in the immune system. We propose a new integrative systems approach to analyze STAT-STAT interactions in the immune response. The model developed in this study suggests that the T cell plasticity is due to the competition between the intracellular STAT pathways. We studied STAT-STAT interactions in the context of human immune-related diseases such as rheumatoid arthritis, inflammatory bowel disease and systemic lupus erythematosus and discuss the potential therapeutic implications of the proposed model in these diseases. The predictions of the model proposed in this study are supported by experimental data for IFN-γ and IL-10 production.