A temporally dynamic Foxp3 autoregulatory transcriptional circuit controls the effector Treg programme

Abstract

Regulatory T cells (Treg) are negative regulators of the immune response.Whilst thymic Treg generation is well studied, it is not known whether and how Collectively, our study dissects time-dependent mechanisms behind Foxp3-driven T cell regulation, and establishes the Foxp3-Tocky system as a tool to investigate the mechanisms behind T cell immunotherapies.

From stability to dynamics: understanding molecular mechanisms of regulatory T cells throughFoxp3transcriptional dynamics

“…Using Nr4a3 –Tocky, we have shown that Foxp3 expression in the thymus occurs in T cells that have received temporally persistent TCR signals . Furthermore, using Foxp3 –Tocky we showed that Foxp3 transcription is initiated in non‐T reg cells during inflammation in the periphery . In humans, activation‐induced Foxp3 in conventional T cells suppresses their proliferation and cytokine production in a cell‐intrinsic manner .…”

“…As the immunosuppressive T reg population is commonly identified by the expression of Foxp3 (as Foxp3 + T cells in mice and Foxp3 high CD45RA + or Foxp3 + CD127 – CD25 high T cells in humans), the investigation of Foxp3 dynamics in vivo , especially during immune responses, will be key for understanding the in‐vivo dynamics of T reg and T cell regulation. To this end, we have recently developed a new technology, the Timer of cell kinetics and activity (Tocky) system, which allows the investigation of invivo dynamics of Foxp3 and T regs during physiological immune responses .…”

“…Timer proteins exhibit a short‐lived blue fluorescent form, before maturation to the stable red state . The half‐life of blue fluorescence is ~ 4 h and that of the mature red fluorescence is ~ 5 days . Thus, blue and red fluorescence (blue and red) provide a measurement of both the ‘real‐time’ activity and the history of gene transcription .…”

“…The half‐life of blue fluorescence is ~ 4 h and that of the mature red fluorescence is ~ 5 days . Thus, blue and red fluorescence (blue and red) provide a measurement of both the ‘real‐time’ activity and the history of gene transcription . Tocky uses this information to analyse dynamic changes quantitatively in transcriptional activities during cellular activation and differentiation .…”

“…In the TGF‐β‐rich microenvironment, such as in the intestines, tumour or damaged tissues undergoing regeneration and remodelling, the persistence of pathogen or autoantigen may activate monocytes and dendritic cells, and thereby repress Foxp3 transcription and promote Th17 differentiation, as observed in rheumatoid arthritis patients . In contrast, once the activation of innate immune cells is terminated, Foxp3 transcription may be initiated in antigen‐reactive T cells, as observed by Foxp3 –Tocky , especially when adjacent T cells are proliferating and producing IL‐2, inducing the resolution of inflammation.…”