The transcription factor Foxp1 preserves integrity of an active Foxp3 locus in extrathymic Treg cells

Abstract

Regulatory T (Treg) cells, which are broadly classified as thymically derived (tTreg) or extrathymically induced (iTreg), suppress immune responses and display stringent dependence to the transcription factor Foxp3. However precise understanding of molecular events that promote and preserve Foxp3 expression in Treg cells is still evolving. Here we show that Foxp1, a forkhead transcription factor and a sibling family member of Foxp3, is essential for sustaining optimal expression of Foxp3 specifically in iTreg cells. Deletion of Foxp1 renders iTreg cells to gradually lose Foxp3, resulting in dramatically reduced Nrp1−Helios− iTreg compartment as well as augmented intestinal inflammation in aged mice. Our finding underscores a mechanistic module in which evolutionarily related transcription factors establish a molecular program to ensure efficient immune homeostasis. Furthermore, it provides a novel target that can be potentially modulated to exclusively reinforce iTreg stability keeping their thymic counterpart unperturbed.

Large-Scale Generation of Human Allospecific Induced Tregs With Functional Stability for Use in Immunotherapy in Transplantation

“…For example, FOXP1 transcription factor is required for the optimal expression of FOXP3 in iTregs but is independent of the cell division and methylation status of the TSDR FOXP3 region. Moreover, the absence of FOXP1 does not affect the methylation status of FOXP3, but rather the chromatin modification of the FOXP3 locus (52). In addition, in TGF-β1-induced iTregs, there is an increase in the trimethylation of histone H3K4, even in the absence of hypomethylation (53).…”

Foxp1 is critical for the maintenance of regulatory T-cell homeostasis and suppressive function

“…It is an intriguing question whether Foxp1 is important for both tTreg cells and iTreg cells. Recently, Ghosh and colleagues showed that Foxp1 is vital for the iTreg cell differentiation and functions but is dispensable for the function of tTreg cells [48]. However, by using the same Foxp1 f/f mouse line, Konopacki and colleagues showed that Foxp1 has an essential function in regulating tTreg cells [49].…”

TGF-β signaling controls Foxp3 methylation and T reg cell differentiation by modulating Uhrf1 activity

“…In addition, Obata et al (2014) found that Uhrf1 facilitated colonic T reg cell proliferation to restrain colitis, while our data demonstrated that Uhrf1 inhibited iT reg cell differentiation to keep the identity of conventional T cells. Notably, increasing evidence suggested that the same factors might play distinct roles in different T reg cell subsets (Pabbisetty et al, 2014;Kitagawa et al, 2017;Wu et al, 2017;Ghosh et al, 2018). Colonic T reg cells and iT reg cells were generated in different locations and in response to different environmental signals (Zhou et al, 2009;Josefowicz et al, 2012;Arpaia et al, 2013;Furusawa et al, 2013;Luu et al, 2017), and a single-cell transcriptomics study showed that T reg cells generated from lymphoid organs and colon were quite heterogeneous, which might be due to their adaptation to the local environments (Miragaia et al, 2019).…”