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

Ildar I Sadreev; Michael Z Q Chen; Yoshinori Umezawa; Vadim N Biktashev; Claudia Kemper; Diana V Salakhieva; Gavin I Welsh; Nikolay V Kotov

arXiv · 1701.05503

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

Ildar I Sadreev·Michael Z Q Chen·Yoshinori Umezawa·Vadim N Biktashev·Claudia Kemper·Diana V Salakhieva·Gavin I Welsh·Nikolay V Kotov

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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.

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Ildar I Sadreev, Michael Z Q Chen, Yoshinori Umezawa, Vadim N Biktashev, Claudia Kemper, Diana V Salakhieva, Gavin I Welsh, Nikolay V Kotov. 2017-01-19. The competitive nature of STAT complex formation drives phenotype switching of T cells. https://arxiv.org/abs/1701.05503

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