An Inherently Bifunctional Subset of Foxp3+ T Helper Cells Is Controlled by the Transcription Factor Eos

Abstract

SUMMARY At sites of inflammation, certain regulatory T cells (Treg cells) can undergo rapid reprogramming into helper-like cells, without loss of the transcription factor Foxp3. We show that reprogramming is controlled by down-regulation of the transcription factor Eos (Ikzf4), an obligate co-repressor for Foxp3. Reprogramming was restricted to a specific subset of “Eoslabile” Treg cells which were present in the thymus and identifiable by characteristic surface markers and DNA methylation. Mice made deficient in this subset became impaired in their ability to provide help for presentation of new antigens to naive T cells. Down-regulation of Eos required the pro-inflammatory cytokine IL-6, and mice lacking IL-6 had impaired development and function of the Eos-labile subset. Conversely, the immunoregulatory enzyme IDO blocked loss of Eos, and prevented the Eos-labile Treg cells from reprogramming. Thus, the Foxp3+ lineage contains a committed subset of Treg cells capable of rapid conversion into biologically important helper cells.

Foxp3+ T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation

“…It has been argued that downmodulation of Eos (encoded by Ikzf4) transcription is indicative of Tregs undergoing reprogramming into T helper-like cells. 54 However, the overall methylation pattern in the Treg-specific epigenetic signature genes in Foxp3 þ RORgt þ T cells may rather support the idea that a fraction of Foxp3 þ RORgt þ T cells are peripherally induced and are on the way to acquire full demethylation in their Tnfrsf18 and Ikzf4 loci, as recently suggested. 40 Further supporting this hypothesis, we also found a mixed pattern of Helios expression in Foxp3 þ RORgt þ T cells, indicating that the Foxp3 þ RORgt þ T cells observed under physiologic conditions may be a mixture of not only thymic but also peripherally induced origin, especially in the gut-associated tissues.…”

Human lung tumor FOXP+ Tregs upregulate four “Treg-locking” transcription factors

“…In agreement with earlier work (27), IDO may be the best candidate regulatory factor for Tregs in the LC microenvironment, since it showed the highest differences between tumors and all other samples, including distant lungs. Interestingly, IDO was previously shown to prevent loss of EOS in Tregs and therefore to block their reprogramming into T helper-like cells in inflammatory conditions in mice (53). This relationship as part of the tumor microenvironment will be studied in our future work.…”

CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

“…Moreover, the CD154 + Foxp3 + CD4 + T cell subset expressed the proinflammatory cytokine TNF-a, supporting the functional change of the Foxp3 + CD4 + T cells. In a recent study by Sharma et al (38) it has also been demonstrated that in response to specific inflammatory signals, Foxp3 + CD4 + T cells were transformed into biologically important helper cells, without loss of Foxp3. However, it has not been addressed so far whether Foxp3 + CD4 + T cells can undergo conversion that will change their functional capability and turn them into cytotoxic CD4 + T cells.…”