The competitive nature of signal transducer and activator of transcription complex formation drives phenotype switching of T cells

Abstract

Signal transducers and activators of transcription (STATs) are key molecular determinants of T-cell fate and effector function. Several 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 by which 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 modelling and experimental data for intracellular STAT signalling 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 the result of 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 interferon-γ to interleukin-10 switching that regulates human T helper type 1/type 1 regulatory T-cell responses. The proposed model is applicable to a number of STAT signalling circuits.

Batf-mediated Epigenetic Control of Effector CD8+ T Cell Differentiation

“…Unlike most other TFs we profiled, the changes in the binding of Stat3 in the absence of Batf did not have a strong association with changes to accessibility. This may suggest other means in which Batf exerts its effects in Stat3 sites, such as changes in the activity of binding competitors (Sadreev et al, 2018; Walker et al, 2013; Wingelhofer et al, 2018) and/or in post translational modifications at nearby histone tails (Chan and Maze, 2020). Notably, we observed a similar trend of low correlation between changes in binding versus changes in accessibility in the case of Fosl2.…”

Role of the JAK/STAT Pathway in Cervical Cancer: Its Relationship with HPV E6/E7 Oncoproteins

“…For example, it is known that STAT4/STAT1 can form heterodimers in response to IL-35, an immunosuppressive cytokine associated with the generation of Tregs and with poor prognosis in some types of cancer. It is possible that the STAT4/STAT1 heterodimer may be related to anti-inflammatory programs [ 114 , 115 , 116 , 117 ]. There are intrinsic factors responsible for such vast plasticity to the transcriptional outcome generated by the JAK/STAT signaling pathway, and thus the response elicited by a cell or tissue.…”

A functional different immune capacity in cattle is associated with higher mastitis incidence

“…The effect of STAT1 inhibition could not be tested, since we found no STAT1 specific inhibitor that was commercially available. In mice and man, STAT1 is important for the differentiation of naive CD4 + T cells to Th1 cells (28) or to type 1 regulatory (Tr) T cells (29). From these findings, we conclude that after immune stimulation, control lymphocytes use the STAT1 pathway and we hypothesize that control cows react with a Th1 or Tr immune response in polyclonal stimulation assays.…”