A novel function for FOXP3 in humans: intrinsic regulation of conventional T cells

Abstract

Key Points• FOXP3 functions as a negative regulator of T-cell proliferation and cytokine production in human conventional T cells.• Expression of FOXP3 in human Th17 cells functions to suppress IFN-␥ production. IntroductionExpression of the transcription factor forkhead box P3 (FOXP3) in T-regulatory cells (Tregs) is necessary and sufficient for Tregs to suppress the effector function of conventional T (Tconv) cells. In cooperation with other transcription factors, including NFAT and Runx1, and the Th17-associated transcription factors ROR-␥t and ROR␣, FOXP3 establishes the Treg program by repressing or trans-activating defined genes. 1,2 The molecular mechanisms of FOXP3-mediated regulation of gene transcription are not clearly defined, but repression involves interactions with the histone acetyl-transferase TIP60, the histone deacetylase HDAC7, and linker histone H1.5. 3,4 After its discovery in Tregs, it was soon demonstrated that FOXP3 is also expressed transiently in human Tconv cells after TCR activation. [5][6][7][8][9][10][11] Similarly, another Treg-associated transcription factor, Helios, can also be expressed on activation. 12 The major differences between FOXP3 in Tregs and Tconv cells are in stability and expression levels. In Tregs, the Treg-specific demethylated region (TSDR) region of the FOXP3 promoter is demethylated, permitting high and stable expression. 13 Conversely, in Tconv cells, the TSDR is methylated, resulting in transient expression of FOXP3 that never reaches the intensity of that in similarly activated Tregs. 6,7,9,13 Transient FOXP3 expression in Tconv cells does not prevent cytokine production and/or confer suppressive capacity, although this has been a point of controversy. [5][6][7][8][9][10][11] Another role for FOXP3 is to antagonize Th17 cell development. Interaction of FOXP3 with ROR-␥t or Runx1 inhibits IL-17 production, 1 whereas ROR-␥t together with hypoxia-inducible factor 1␣ inhibits FOXP3. 14 Therefore, in a tolerogenic environment that includes TGF␤, FOXP3 suppresses Th17 cell development and Treg differentiation prevails. In contrast, in inflammatory environments hypoxia inducible factor1␣ promotes ROR-␥t expression, causing degradation of FOXP3, promotion of Th17 cell development, and blockade of Treg differentiation. 14 Beyond this "tug-of-war" during differentiation, Tregs and Th17 cells may have the ability to interconvert. FOXP3 ϩ IL-17-secreting cells exist in vivo, 15-17 but it is not clear whether these cells are Tregs that have begun to secrete IL-17 or if they are Th17 cells that have begun to express FOXP3.Despite clear evidence that FOXP3 is expressed in Tconv cells, its function remained unknown. In the present study, we investigated the role of FOXP3 in human Tconv cells and found that FOXP3-deficient Tconv cells proliferated to a greater extent and produced greater amounts of cytokines than wild-type (WT) Tconv cells. Furthermore, FOXP3 was highly expressed in activated Th17 The online version of this article contains a data supplement.The publicati...

Foxp3-independent mechanism by which TGF-β controls peripheral T cell tolerance

“…However, it remains possible that TGF-β inhibition of T cell activation and differentiation is dependent on transient expression of Foxp3 induced by TGF-β signaling (13,15,16). Indeed, Foxp3 induction in conventional human CD4 + CD25 − T cells has been demonstrated to inhibit T cell proliferation and affect gene expression (17,18). Furthermore, Treg cells may engage the TGF-β pathway to promote T cell tolerance via TGF-β production and activation of the latent form of TGF-β (19)(20)(21)(22).…”

Forkhead box P3: The Peacekeeper of the Immune System

“…[33,34], although it has been associated with suppression of the cytokine production and proliferation of multiple CD4 + T cell lineages [33,35]. Indeed, FOXP3-deficient Teff cells proliferate more, produce more cytokines than wild type Teff cells, and activation-induced FOXP3 expression is sustained in Th17 cells, suggesting that FOXP3 contributes to the developmental program of human Th17 cells [35].…”

Harnessing FOXP3+ regulatory T cells for transplantation tolerance

“…The fact that CD4 T cells can transiently or "promiscuously" express FOXP3 may also be relevant to therapeutic induction of tolerance. It has long been known that ectopic FOXP3 expression can turn down inflammatory cytokine production and damaging effector functions including graft rejection (9,(44)(45)(46). On this basis, treatments that turn on FOXP3 expression and function, even transiently, may help ensure a temporary ceasefire, perhaps paving the way for stable regulation to evolve over time.…”

“…It is here that the molecular mechanisms involved in FOXP3 expression, outlined above, are integrated. Although transient expression of FOXP3 may be insufficient to establish stable Tregs, it may contribute to the restraint (9,45,46), and even apoptosis (104), of potential effector cells and thus support the drug-initiated ceasefire. This buys the necessary time (105) for some FOXP3-converted cells to undergo the epigenetic changes that eventually stabilize them (52).…”

“…A proportion of these FOXP3-expressing cells will continue differentiation toward mature pTregs with a well-established Treg-specific epigenome. Meanwhile, even those T cells transiently expressing FOXP3 will be restrained from participation in the inflammatory (rejection) process (9,(44)(45)(46). As the therapeutic agents clear from the system, the favorable balance of regulation (based on expanded antigen-specific tTregs and pTregs) creates the third stage of "operational tolerance" (right).…”