Id3 Maintains Foxp3 Expression in Regulatory T Cells by Controlling a Transcriptional Network of E47, Spi-B, and SOCS3

Katharina S Rauch,Miriam Hils,Ekaterina Lupar,Susana Minguet,Mikael Sigvardsson,Martin E Rottenberg,Ana Izcue,Christian Schachtrup,Kristina Schachtrup

doi:10.1016/j.celrep.2016.11.045

Abstract

The transcription factor Foxp3 dominantly controls regulatory T (Treg) cell function, and only its continuous expression guarantees the maintenance of full Treg cell-suppressive capacity. However, transcriptional regulators maintaining Foxp3 transcription are incompletely described. Here, we report that high E47 transcription factor activity in Treg cells resulted in unstable Foxp3 expression. Under homeostatic conditions, Treg cells expressed high levels of the E47 antagonist Id3, thus restricting E47 activity and maintaining Foxp3 expression. In contrast, stimulation of Id3-deficient or E47-overexpressing Treg cells resulted in the loss of Foxp3 expression in a subset of Treg cells invivo and invitro. Mechanistic analysis indicated that E47 activated expression of the transcription factor Spi-B and the suppressor of cytokine signaling 3 (SOCS3), which both downregulated Foxp3 expression. These findings demonstrate that the balance of Id3 and E47 controls the maintenance of Foxp3 expression in Treg cells and, thus, contributes to Treg cell plasticity.

Highlights

CD4+Foxp3+ regulatory T (Treg) cells are crucial for maintaining immune homeostasis and peripheral tolerance due to their ability to suppress T cell responses
The decreased Foxp3 expression in Id3À/À cells was greatest in Id3À/À Treg cells that had not divided and, was not due to increased abundance of contaminating and proliferating Foxp3À cells (Figure 1C), nor was it due to increased cell death, as we did not detect any differences in the amount of viable cells after 3 days of stimulation (Figure S1C)
The abundance of Ctla4 and Irf4 transcripts was comparable in WT and Id3À/À CD62Lhi Treg cells, and Irf4 expression was reduced compared to bulk Treg cells, confirming that we isolated naive-like Treg cells and that WT and Id3À/À cells had a similar activation status (Figure S1D)

Summary

Introduction

CD4+Foxp3+ regulatory T (Treg) cells are crucial for maintaining immune homeostasis and peripheral tolerance due to their ability to suppress T cell responses. The transcription factor Foxp is critical for Treg cell development and instrumental in maintaining full Treg cell function (Sawant and Vignali, 2014). Initiation and maintenance of Foxp expression are tightly controlled epigenetically and by various transcriptional regulators (Huehn and Beyer, 2015). The CNS2 region contains several demethylated CpG islands in committed Treg cells and, guarantees heritable maintenance of Foxp expression (Huehn and Beyer, 2015). Foxp3+ Treg cells have been suggested to dedifferentiate into Foxp3À effector T cells, losing their suppressive capacity and producing proinflammatory cytokines (Sawant and Vignali, 2014)

Results

Discussion

Conclusion