Disease relevance of FOXP3

• Reduced frequency of FOXP3+ CD4+CD25+ regulatory T cells in patients with chronic graft-versus-host disease [1].
• Decreased FOXP3 levels in multiple sclerosis patients [2].
• FOXP3, a characteristic marker for CD4+CD25+ Tr cells, TGF-beta1 and IL-10 were expressed more highly in periodontitis compared with gingivitis [3].
• A point mutation in the forkhead domain of FOXP2 (R553H) is responsible for a severe speech and language disorder, while a series of missense mutations distributed over the forkhead domain of FOXP3 cause a fatal disorder called IPEX, characterized by immune dysregulation, polyendocrinopathy, and enteropathy [4].
• Similarly, 24-h incubation with supernatants from cyclooxygenase-2-overexpressing lung cancer cells that secrete high levels of PGE2 significantly induced FOXP3 in CD4+CD25- T cells [5].

High impact information on FOXP3

• FOXP3 controls regulatory T cell function through cooperation with NFAT [6].
• IPEX is a fatal disorder characterized by immune dysregulation, polyendocrinopathy, enteropathy and X-linked inheritance (MIM 304930) [7].
• Upregulation of TGF-beta, FOXP3, and CD4+CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection [8].
• Foxp3 and Aire in thymus-generated T(reg) cells: a link in self-tolerance [9].
• Erratum: A function for interleukin 2 in Foxp3-expressing regulatory T cells [10].

Chemical compound and disease context of FOXP3

• For testing the in vivo significance of this effect, CD4(+)CD25(+) T cells that expressed high levels of Foxp3 were reconstituted into SCID mice after induction of Adriamycin nephropathy, a noncognate model of chronic renal disease [11].

Biological context of FOXP3

• Gene expression of Treg transcription factor FOXP3 was reduced in cGVHD patients compared with patients without cGVHD (P = .009) or healthy donors (P = .01) [1].
• Mutations of the forkhead/winged helix transcription factor FOXP3 gene on chromosome Xp11.23 cause a rare recessive monogenic disorder called IPEX (immune dysregulation, polyendocrinopathy, including type 1 diabetes, enteropathy, and X-linked syndrome) [12].
• FOXP3 is playing an essential role for T regulatory cells and is involved in the molecular mechanisms controlling immune tolerance [13].
• The basal promoter contains six NF-AT and AP-1 binding sites, which are positively regulating the trans activation of the FOXP3 promoter after triggering of the TCR [13].
• The FOXP3 promoter was defined by RACE, cloned, and functionally analyzed using reporter-gene constructs in primary human T cells [13].

Anatomical context of FOXP3

• Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD [14].
• We used linkage analysis, mutational screening of the FOXP3 gene, human leukocyte antigen typing, and analysis of X-chromosome inactivation to investigate 2 kindreds (21 subjects in total) with 4 male infants (3 now deceased) and 1 girl affected by IPEX [15].
• In order to better define the role of FOXP3 in human Teff cells, we investigated the intensity and kinetics of expression in ex vivo Teff cells, suppressed Teff cells and Teff cell lines [16].
• This is the first report indicating that PGE2 can modulate FOXP3 expression and T reg function in human lymphocytes [5].
• Induction of FOXP3-expressing regulatory CD4pos T cells by human mature autologous dendritic cells [17].

Associations of FOXP3 with chemical compounds

• Furthermore, the study identifies essential, positive regulators of the FOXP3 gene and highlights cyclosporin A as an inhibitor of FOXP3 expression contrasting other immunosuppressants such as steroids or rapamycin [13].
• Future studies will evaluate the effects of therapies known to influence Treg cell function and FOXP3 expression, including TCR peptide vaccination and supplemental estrogen [2].
• FOXP3 mRNA levels were inversely correlated with serum creatinine levels measured at the time of biopsy in the acute-rejection group (Spearman's correlation coefficient = -0.38, P=0.02) but not in the group with chronic allograft nephropathy or the group with normal biopsy results [18].
• FOXP3-positive T(R) represent a novel marker for identifying late-relapse patients who may benefit from aromatase therapy after standard tamoxifen treatment [19].
• Proliferation in the presence or absence of oxidized LDL (oxLDL) was evaluated by thymidine incorporation. mRNA and protein content of foxp3, a master transcriptional regulator of Tregs, were determined for all subjects [20].

Physical interactions of FOXP3

• Using chromatin immunoprecipitation, we have demonstrated that Foxp3 binds to the endogenous IL-2 and IFNgamma loci in T cells, but only after T cell receptor stimulation [21].

Regulatory relationships of FOXP3

• Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells [22].
• Further, BV-LPS induced CD25 and Foxp3 expression in lymphocytes and CD4(+)CD25(+) cells expressed IL-10 mRNA [23].
• In the present work, we demonstrate that Foxp3 can induce heme oxygenase-1 (HO-1) expression and subsequently such regulatory phenotypes as the suppression of nontransfected cells in a cell-cell contact-dependent manner as well as impaired proliferation and production of cytokines upon stimulation in Jurkat T cells [24].
• The identification of transcription factors controlling Th1, Th2 and T-regulatory cell (T(Reg)) development further support the Th2 hypothesis since GATA3 is overexpressed and T-bet underexpressed in the asthmatic airway and Foxp3 is induced in asthma by corticosteroid treatment [25].
• Blocking ILT-3 or IL-12 does not diminish the capacity of these DCs to induce regulation or Foxp3 expression on the regulatory T cells [26].
• Ectopic expression of FOXP3 in mouse mammary cancer cells repressed SKP2 expression with a corresponding increase in p27 and polyploidy [27].
• FOXP3 can be acetylated in primary human regulatory T cells, and TIP60 promotes FOXP3 acetylation in vivo [28].

Other interactions of FOXP3

• We have also shown that binding of Foxp3 to the IL-2 and IFNgamma genes induces active deacetylation of histone H3, a process that inhibits chromatin remodeling and opposes gene transcription [21].
• Disease-causing mutations in FOXP2 and FOXP3 map either to the DNA binding surface or the domain-swapping dimer interface, functionally corroborating the crystal structure [29].
• BACKGROUND: The transcription factor FOXP3 has been identified as the molecule associated with the regulatory function of CD25+ T cells [30].
• Our study is the first to establish that MS patients have abnormalities in FOXP3 message and protein expression levels in peripheral CD4+ CD25+ T cells (Tregs) that are quantitatively related to a reduction in functional suppression induced during suboptimal T-cell receptor (TCR) ligation [2].
• The expression of Foxp3, CTLA-4, and ICOS mRNAs in PBMCs stimulated with bovine or human insulin was higher in patients on insulin treatment than in patients studied before starting insulin treatment [31].
• The blockade of CD27-CD70 interaction by anti-CD70 Ab abrogated lymphoma B-cell-mediated induction of Foxp3 expression in intratumoral CD4(+)CD25(-) T cells [32].
• Transfection of FOXP3-deficient CD4(+)CD25(+) T cells from patients with a plasmid encoding wild-type NFAT1 resulted in increased FOXP3 expression in these cells [33].

Analytical, diagnostic and therapeutic context of FOXP3

• After clinical heart transplantation the highest FOXP3 mRNA expression levels were measured in biopsies during acute rejection (P=0.03) [30].
• The effect of immunosuppressive drugs on FOXP3 expression was studied in mixed lymphocyte reactions (MLR) in the presence and absence of calcineurin inhibitors (CNI), alphaCD25 mAb, and Rapamycin (Rapa), and analyzed in biopsies from cardiac allograft recipients during acute rejection by quantitative (Q)-PCR [30].
• Moreover, only one single FOXP3 transcript was expressed by CD4 T cell clones analysed by RT-PCR, confirming that this gene is subject to X- inactivation [34].
• The samples were analyzed by flow cytometry to determine the frequency of Tr cells and by real-time PCR for forkhead box P3 (FOXP3) expression [35].
• Cell proliferation and death, Foxp3, intracellular pH, and cytokine production were evaluated by flow cytometry [36].

References