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

TL;DR

This study combines mathematical modeling and experimental data to uncover how STAT protein competition influences T cell phenotype switching, revealing a mechanism for immune response plasticity relevant to inflammatory diseases.

Contribution

It introduces a novel model explaining T cell phenotype switching through STAT competition, advancing understanding of immune cell plasticity and potential therapeutic targets.

Findings

Model accurately predicts IFN-γ to IL-10 switching

T cell switching driven by redistribution of STAT dimers

Applicable to various STAT signaling pathways

Abstract

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 for IFN-{\gamma} to IL-10 switching allows us to propose a potential mechanism for T cell switching that regulates human Th1/Tr1 responses. 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 proposed model is applicable to a number of STAT signaling circuits.