One recently documented signaling pathway involved in Foxp3 expression is the PI3K-Akt-mTOR axis. Retroviral transduction of an active form of Akt impairs Foxp3 induction by TGF-β, which was reversed by the mTOR inhibitor Rapamycin [44
]. A PI3K inhibitor LY294002 induces Foxp3 expression without the need of TGF-β stimulation, whereas loss of the lipid phosphatase Pten causes a reduction of Foxp3 expression in response to treatment with TGF-β or PI3K inhibitor [45
]. It seems that such inhibition is independent of TGF-β signaling but affects the histone modification of both the Foxp3 basic promoter and enhancer regions in the first intron encompassing the Stat5/CREB-binding sites [45
Notch signaling pathway plays a pivotal role in cell fate decisions of many tissues including the lineage decisions of lymphocytes like Th1 vs Th2 cells. Expression of Jagged1, a ligand for Notch1, in antigen-presenting cells, induces naïve CD4+ T cells into Tregs [46
]. Similarly, Jagged-2-expressing hematopoietic progenitors promote Treg expansion via activating Notch3 [47
]. In addition, expression of a stabilized form of β-catenin, a mediator of Wnt- or frizzled-signaling pathway, enhances the survival of Tregs [48
], suggesting that this evolutionarily conserved pathway in cell differentiation and development also plays a role in Treg regulation.
One recent breakthrough in studying Foxp3 expression is the discovery of retinoic acid (RA), a vitamin A metabolite, induces Foxp3 expression in synergy with TGF-β [49
]. RA is generated in functionally specialized mucosal DCs, which, when co-cultured with naïve CD4+ T cells, converts them into Foxp3+ T cells, whereas addition of either anti-TGF-β or RA antagonist abrogates the Foxp3 induction by this DC subset. More importantly, in vitro-generated Tregs by TGF-β and RA are more effective in preventing mice from colitis than the cells with only TGF-β treatment.
In addition to its effect on Tregs, TGF-β also induces the differentiation of Th17 cells in the presence of a pro-inflammatory cytokine, IL-6 [17
]. In a sharp contrast to Tregs, which actively suppress immune responses, Th17 cells are involved in promoting autoimmune and inflammatory responses. Intriguingly, RA inhibits Th17 differentiation [51
] by reducing the expression of RORγt, a master transcription factor for Th17 cells [53
]. Recent studies have documented that Foxp3 suppresses Th17 differentiation by antagonizing RORγt function [54