E-protein regulatory network links TCR signaling to effector Treg cell differentiation

Abstract

T cell antigen receptor (TCR) signaling is essential for the differentiation and maintenance of effector regulatory T (Treg) cells. However, the contribution of individual TCR-dependent genes in Treg cells to the maintenance of immunotolerance remains largely unknown. Here we demonstrate that Treg cells lacking E protein undergo further differentiation into effector cells that exhibit high expression of effector Treg signature genes, including IRF4, ICOS, CD103, KLRG-1, and RORγt. E protein-deficient Treg cells displayed increased stability and enhanced suppressive capacity. Transcriptome and ChIP-seq analyses revealed that E protein directly regulates a large proportion of the genes that are specific to effector Treg cell activation, and importantly, most of the up-regulated genes in E protein-deficient Treg cells are also TCR dependent; this indicates that E proteins comprise a critical gene regulatory network that links TCR signaling to the control of effector Treg cell differentiation and function.

The transcriptional regulator Id2 is critical for adipose-resident regulatory T cell differentiation, survival and function

“…Bcl-2 expression and increased cell death of these cells (23). In peripheral Tregs, recent gene expression analysis revealed loss of E proteins resulted in upregulation of proteins associated with proliferation and survival such as Bcl-2, Ki-67 and Bcl-11b (14). Here we showed that Id2 is a critical factor for the survival of aTregs and that loss of Id2 results in upregulation of the pro-apoptotic protein Fas.…”

“…However, the use of non-Treg specific Cre lines and a focus on analysis of the thymically-derived Treg populations, precluded significant advancement in understanding the function of these proteins in aTregs. More recently, E2A and HEB were shown to be critical for effector Tregs with Foxp3-Cre mediated loss of E proteins resulting in substantial increases in Tregs in peripheral tissues such as the small intestine, lung and liver, although the Treg population residing in adipose tissue was not examined (14). The function of Id2 and Id3 in conventional Tregs has also been examined by crossing Id2 and Id3 floxed animals to a Foxp3-Cre line (15).…”

“…IL-10 has been shown to be positively regulated by E proteins in conventional T cells (25). However, in peripheral tissue Tregs it was recently reported that IL-10 is likely negatively regulated by E2A and HEB (14), suggesting that E protein activity in T cells is context-dependent. With loss of Id2 and unchecked E protein activity, we see reduced IL-10 production, suggesting that 1) IL-10 is negatively regulated by E2A and HEB in aTregs and 2) loss of Id2 in aTregs reduces their ability to suppress local and systemic inflammation, resulting in perturbed glucose tolerance.…”

Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting?

“…Briefly, Interferon Regulatory Factor 4 (IRF4), Myb, and Nuclear Factor Kappa-light-chain-enhancer of activated B cells (NF-κB) seem to kick-start the aTreg specification program [24][25][26][27], whereas Basic Leucine Zipper Transcription Factor (BATF), B-lymphocyte-induced maturation protein 1 (Blimp1), JunB, and Myb are then required to establish and maintain the aTreg landscape [24,28]. Importantly, negative regulators of the aTreg program have been described, such as Forkhead Box protein O (Foxo) or E-protein transcription factors [29,30]. At a more advanced level of differentiation, aTreg cells can acquire the expression of tissue-or microenvironment-induced transcription factors historically linked to the polarization of Tconv cells into Thelper (TH) subsets.…”

“…E-proteins are transcriptional activators and repressors, the activity of which is inhibited by Id proteins. The E-proteins E2A and HEB inhibit the transition to the aTreg cell state [29]. Consequently, conditional ablation of E2A and HEB in mature Treg cells, leads to the accumulation of highly suppressive aTreg cells in the periphery [29].…”