Fig. 3: Upstream and downstream regulation of FOXP3.
The transcriptional and epigenetic modifications that control Forkhead box P3 (FOXP3) expression, where blue arrows signify upregulation while red arrows signify repression of its target. Blue boxes mean the protein increases FOXP3 expression, while red boxes mean the protein downregulates FOXP3 expression. Transcriptional modifications that upregulate FOXP3 expression include: (i) Interleukin-2 (IL-2) binding to Cluster of Differentiation 25 (CD25) to activate Signal Transducer and Activator of Transcription 5 (STAT5)50. (ii) T-cell Receptor (TCR) activates a pathway consisting of Forkhead box O (FOXO), Nuclear Factor of Activated T cells (NFAT), and Activator Protein-1 (AP-1)42. This TCR signal can also lead to lower FOXP3 expression through activation of Mammalian Target of Rapamycin (mTOR) or complex consisting of Suppressor of Cytokine Signaling 3 (SOCS3) and Spi-B transcription factor (Spib). (iii) Transforming Growth Factor Beta (TGFβ) activates the SMAD-dependent pathway (SMAD2/3) directly or through the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) pathway. SMAD-independent pathways are activated through TGFβ-activated kinase 1 (TAK1) or FOXO3/NFAT/AP-1 pathways43; (iv) C-C Motif Chemokine Ligand (CCL1) binds to C-C Motif Chemokine Receptor 8 (CCR8) to induce STAT3-dependent upregulation of FOXP3148. FOXP3 expression is epigenetically and post-translationally altered through ubiquitination, phosphorylation, and methylation, which lowers expression, and acetylation, which increases expression. IL-1β or lipopolysaccharide (LPS) binding to Toll-like Receptor 4 (TLR4) can activate STIP1 Homology and U-box Containing Protein 1 (Stub1), leading to lysine 48-linked FOXP3 ubiquitination55. Alternatively, IL-6 stimulation can decrease FOXP3 expression by increasing ubiquitination through hypoxia-inducible factor 1 alpha (HIF1α) activation56, or modulating chromatin binding by reversing TGFβ-induced FOXP3 acetylation149. Proviral Integration site in Moloney murine leukemia virus family kinase 1 and 2 (PIM1/2) can phosphorylate FOXP3 in the N-terminal to reduce protein expression and reduced suppression150. IL2 stimulation can also demethylate FOXP3 through upregulation of Tet methylcytosine dioxygenase 2 (TET2)151. Epigenetic and transcriptional modifications adapted from Qiu et al.152. Downstream from FOXP3, the transcription factor targets are grouped based on gene role in Treg suppression, reducing inflammation, and Treg stability. Red X over black arrow means FOXP3 represses the transcription of the target gene. FOXP3 target genes adapted from CHIPseq analysis40,41. NT5E 5’-Nucleotidase, PRDM1 PR domain zinc finger protein 1, FASL Fas ligand, CTLA4 Cytotoxic T-lymphocyte Antigen 4, GZM granzyme, GITR glucocorticoid-induced Tumor necrosis factor receptor-related protein, IFNγ interferon gamma, JAK2 janus kinase 2, PTPN22 Protein tyrosing phosphatase non-receptor type 22, PDE3B phosphodiesterase 2B, NRP1 neuropilin-1, IRF4 interferon regulatory factor 4, miR micro RNA, TNFRSF9 tumor necrosis factor receptor superfamily member 9. The figure was created in BioRender. Tavasolian, F. (2026) https://BioRender.com/fe0m2na.
