Regulatory T cells (Tregs), characterized by the expression of Forkhead Box P3 (FOXP3), constitute a distinct subset of T cells crucial for immune regulation. Tregs can exert direct and indirect control over immune homeostasis by releasing inhibitory factors or differentiating into Th-like Treg (Th-Treg), thereby actively contributing to the prevention and treatment of autoimmune diseases. The epigenetic regulation of FOXP3, encompassing DNA methylation, histone modifications, and post-translational modifications, governs the development and optimal suppressive function of Tregs. In addition, Tregs can also possess the ability to maintain homeostasis in diverse microenvironments through non-suppressive mechanisms. In this review, we primarily focus on elucidating the epigenetic regulation of Tregs as well as their multifaceted roles within diverse physiological contexts while looking forward to potential strategies involving augmentation or suppression of Tregs activity for disease management, particularly in light of the ongoing global COVID-19 pandemic.

OBJECTIVE: Tumor initiating cells (TICs) or cancer stem cells (CSCs) are considered to be the main culprit of hepatocellular carcinoma (HCC) initiation and progression, nevertheless the mechanism by which tumor microenvironment maintains the HCC \'stemness\' is not fully understood. This study aims to investigate the effect of regulatory T cells (Tregs) on the TICs characteristics of HCC.
METHODS: Immunocytochemistry, flow cytometry, real-time PCR, western blot, in vitro sphere-formation, and in vivo tumorigenesis assay were used to detect HCC \'stemness\'. Additionally, after forced expression or inhibition of FoxP3, β-catenin expression and HCC \'stemness\' were investigated.
RESULTS: Tregs enhanced the \'stemness\' of HCC cells by upregulating TIC-related markers CD133, Oct3/4, Sox2, c-Myc, Klf4, Nanog, CD13, EpCAM, and inducting epithelial to mesenchymal transition (EMT), increasing TICs ratio, as well as promoting tumorigenic ability. Moreover, β-catenin and c-Myc were upregulated in HCC cells after co-cultured with Tregs. HCC \'stemness\' was inhibited after treatment with Wnt/β-catenin pathway inhibitor. Furthermore, forced expression of FoxP3 resulted in increased GSK3β, decreased β-catenin and TIC ratio in HCC. In contrast, FoxP3 interference reduced GSK3β, enhanced β-catenin and TIC ratio of HCC.
CONCLUSIONS: This study, for the first time, demonstrated that Tregs increased the population of TICs in HCC by inhibiting FoxP3 as well as promoting β-catenin expression.

BACKGROUND: Chronic idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease characterized by a breakdown of immune tolerance; in ITP, the body\'s immune system mistakenly attacks and destroys platelets. This study aims to investigate the role and underlying mechanisms of FOXP3 in chronic ITP.
METHODS: Flow cytometry was used to detect the proportion of CD4+CD25+FOXP3+ regulatory T cells (Tregs) in CD4+CD25+ T lymphocytes from 20 patients with chronic ITP (CITP), 20 acute ITP (AITP) controls, and 20 healthy individuals.CD4+CD25+ Treg cells were isolated from peripheral blood of patients with CITP using magnetic beads and then treated with phosphate-buffered saline solution or decitabine (a methylation inhibitor) for 48 h. The levels of interleukin-2 (IL-2), IL-10, and transforming growth factor-beta1 (TGF-β1) in the plasma and CD4+CD25+ Treg cells were assessed by Enzyme-linked-immunosorbent serologic assay and quantitative real-time polymerase chain reaction (qRT-PCR). FOXP3 level was measured by qRT-PCR and Western blot analysis. Methylation-specific PCR (MS-PCR) was adopted to detect the status of FOXP3 methylation.
RESULTS: The number of Treg cells and the contents of IL-2, IL-10, and TGF-β1 decreased in patients with CITP, compared to the AITP control group and normal group. FOXP3 expression was reduced and FOXP3 methylation increased in patients with CITP, compared to the AITP control group and normal group. Hypermethylation of FOXP3 promoter led to decrease in FOXP3 level in Treg cells. Inhibition of FOXP3 promoter hypermethylation promoted the secretion of IL-2, IL-10, and TGF-β1 in Treg cells.
CONCLUSIONS: The number of Treg cells in CITP patients decreased, and the hypermethylation of FOXP3 promoter led to reduction of its expression in Treg cells, thus affecting the immune functioning of Treg cells.

Foxp3+ regulatory T cells (Foxp3+ Treg) play a role in regulating various types of tumors, but uncertainty still exists regarding the exact mechanism underlying Foxp3+ Treg activation in gastrointestinal malignancies. As of now, research has shown that Foxp3+ Treg expression, altered glucose metabolism, or a hypoxic tumor microenvironment all affect Foxp3+ Treg function in the bodies of tumor patients. Furthermore, it has been demonstrated that post-translational modifications are essential for mature Foxp3 to function properly. Additionally, a considerable number of non-coding RNAs (ncRNAs) have been implicated in the activation of the Foxp3 signaling pathway. These mechanisms regulating Foxp3 may one day serve as potential therapeutic targets for gastrointestinal malignancies. This review primarily focuses on the properties and capabilities of Foxp3 and Foxp3+Treg. It emphasizes the advancement of research on the regulatory mechanisms of Foxp3 in different malignant tumors of the digestive system, providing new insights for the exploration of anticancer treatments.

In this study, we identified FOXP3 as a transcription factor for lncRNA SNHG1, which exerts a significant protective role against cardiomyocyte hypertrophy. Through DNA-pull down experiments and ChIP analysis, we confirmed that FOXP3 could bind to the promoter of SNHG1. Luciferase reporter and RT-qPCR experiments validated that FOXP3 overexpression promoted SNHG1 expression in cardiomyocytes. Furthermore, in a model of cardiomyocyte hypertrophy, FOXP3 expression was upregulated, particularly in cardiomyocytes. Functional assays demonstrated that FOXP3 overexpression inhibited cardiomyocyte hypertrophy, while FOXP3 knockdown held the opposite effect. Additionally, we revealed that lncRNA SNHG1 acted as a sponge for miR-182, miR-326, and miR-3918, thereby stabilizing FOXP3 mRNA in cardiomyocytes. The protective role of SNHG1 against cardiomyocyte hypertrophy was found to depend on the presence of FOXP3, forming a positive FOXP3/SNHG1 feedback axis. Moreover, we unveiled this positive FOXP3/SNHG1 feedback axis suppressed cardiomyocyte hypertrophy by negatively regulating Parkin-mediated mitophagy. These findings provide novel insights into the molecular mechanisms underlying cardiomyocyte hypertrophy and offer potential therapeutic targets for related interventions.

UNASSIGNED: FOXP3 is a transcription factor that regulates the development and function of Treg, playing an essential role in preventing autoimmune diseases. Variation in FOXP3 can impair the function of Treg cells, thus destroying their inhibitory capacity and leading to autoimmune diseases. This paper investigated whether the three SNPs in the FOXP3 gene (-3279 C/A, -924 A/G and -6054 del/ATT) are associated with systemic lupus erythematosus (SLE) susceptibility in the Han Chinese population.
UNASSIGNED: The study cohort comprised 122 SLE patients and 268 healthy controls. Genotyping was performed by polymerase chain reaction sequence-specific primer (PCR-SSP). Furthermore, we examined the potential clinical manifestations associated with FOXP3 polymorphisms in SLE patients.
UNASSIGNED: The results showed that the -3279 (C > A) was significantly associated with the SLE risk in a homozygote (OR = 3.24, 95% CI = 1.23-8.52, p = .013, AA vs. CC), dominant (OR = 1.68, 95% CI = 1.07-2.65, p = .025, AC + AA vs. CC), recessive (OR = 2.90, 95% CI = 1.12-7.55, p = .023, AA vs. AC + CC) and allelic (OR = 1.72, 95% CI = 1.18-2.53, p = .005, A vs. C) models. In addition, -924 (A > G) was positively associated with SLE risk in the heterozygote (OR = 1.66, 95% CI = 1.04-2.66, p = .033, AG vs. AA) and dominant (OR = 1.59, 95% CI = 1.01-2.49, p = .042, AG + GG vs. AA) models, whereas -6054 (del > ATT) was not associated with SLE. Moreover, the immunological index analysis suggested that decreased complement C4 occurred more frequently in SLE patients carrying the minor allele (A) -3279 (C > A) than those not (p = .005).
UNASSIGNED: We demonstrated that -3279 (C > A) and -924 (A > G) were associated with an increased risk of SLE and the immunological index, indicating that the FOXP3 variation is potentially related to the occurrence and development of SLE.

BACKGROUND: Previous researches have clarified that miR-155 is increased in methicillin-resistant Staphylococcus aureus (MRSA) pneumonia, and modulates Th9 differentiation. Like Th9 cells, Th17 cells were also a subset of CD4+ T cells and involved in MRSA pneumonia progression. This work aimed to investigate the role and mechanism of miR-155 in Th17 differentiation.
METHODS: Bronchoalveolar lavage fluid (BALF) was collected from children with MRSA pneumonia and bronchial foreign bodies. MRSA-infected murine model was established followed by collecting BALF and lung tissues. qRT-PCR, ELISA and flow cytometry were performed to examine the mRNA expression and concentration of IL-17 and the number of Th17 cells in above samples. HE and ELISA were used to evaluate inflammatory responses in lung. Furthermore, CD4+ T cells were isolated from BALF of children for in vitro experiments. After treatments with miR-155 mimic/inhibitor, the roles of miR-155 in Th17/IL-17 regulation were determined. The downstream of miR-155 was explored by qRT-PCR, western blotting, dual luciferase reporter analysis and RIP assay.
RESULTS: The levels of IL-17 and the proportion of Th17 cells were increased in children with MRSA pneumonia. A similar pattern was observed in MRSA-infected mice. On the contrary, IL-17 neutralization abolished the activation of Th17/IL-17 induced by MRSA infection. Furthermore, IL-17 blockade diminished the inflammation caused by MRSA. In vitro experiments demonstrated miR-155 positively regulated IL-17 expression and Th17 differentiation. Mechanistically, FOXP3 was a direct target of miR-155. miR-155 inhibited FOXP3 level via binding between FOXP3 and Argonaute 2 (AGO2), the key component of RNA-induced silencing complex (RISC). FOXP3 overexpression reversed elevated IL-17 levels and Th17 differentiation induced by miR-155.
CONCLUSIONS: miR-155 facilitates Th17 differentiation by reducing FOXP3 through interaction of AGO2 and FOXP3 to promote the pathogenesis of MRSA pneumonia. IL-17 blockade weakens the inflammation due to MRSA, which provides a nonantibiotic treatment strategy for MRSA pneumonia.

A prominent cause of cancer-related fatalities with a poor prognosis is lung adenocarcinoma (LUAD). KIF5A, a crucial member of the kinesin superfamily, is linked to drug resistance in malignancies. This work aims to investigate the mechanism of KIF5A in docetaxel (DTX) resistance in LUAD cells. The results of bioinformatics analysis, qRT-PCR and western blot analysis show that KIF5A, which is involved in the glycolysis pathway, is highly expressed in LUAD and is positively correlated with glycolysis-related genes. We further verify that silencing of KIF5A inhibits DTX resistance, glycolysis, and lactate production in LUAD cells via cell counting kit-8 (CCK-8), flow cytometry, Seahorse XFe 96, lactate, and glucose assays. Mechanistically, KIF5A promotes DTX resistance in LUAD, and this effect is attenuated upon the addition of an LDHA inhibitor. Chromatin immunoprecipitation and dual-luciferase reporter assays reveal that FOXP3 transcriptionally activates KIF5A. Knockdown of FOXP3 reduces lactate production and enhances DTX sensitivity in LUAD, which is restored upon simultaneous overexpression of KIF5A. Our findings reveal that FOXP3 increases DTX resistance in LUAD cells by enhancing lactate production through the upregulation of KIF5A level. In conclusion, our study provides a novel treatment target for improving chemosensitivity in LUAD.

Immunoinflammatory response plays an important role in the pathophysiological process of ischemic stroke (IS). Forkhead box P3 (FOXP3) is a master regulator for immune cells. Polymorphisms of FOXP3 gene might contribute to the susceptibility of IS. This study aimed to explore the association between FOXP3 gene polymorphisms (rs3761548 and rs2232365) and IS susceptibility in the Chinese Han population.
Polymerase chain reaction and Sanger sequencing were used to detect the genotype of FOXP3 gene rs3761548 and rs2232365 polymorphisms.
Smoking, diabetes mellitus (DM), and HBP histories, higher TG and HDL-C levels were more frequently observed in IS patients than in controls. In comparison with rs3761548 GG genotype, GT genotype (OR = 1.573, 95 %CI = 1.030-2.402; adjusted: OR = 1.736, 95 %CI = 1.070-2.817) and GT + TT vs. GG model (OR = 1.581, 95 %CI = 1.0449-2.382; adjusted: OR = 1.720, 95 %CI = 1.074-2.755) of rs3761548 polymorphism was significantly correlated with elevated ischemic stroke susceptibility both at prior and after adjusted by smoking, HBP, DM, TG and HDL-C. Recessive model of rs2232365 polymorphism could elevate the susceptibility of ischemic stroke (OR = 11.962, 95 %CI = 1.144-3.3363; adjusted: OR = 1.876, 95 %CI = 1.016-3.463). Besides, rs3761548 dominant model (OR = 2.757, 95 %CI = 1.379-5.552; adjusted: OR = 2.601, 95 %CI = 1.268-5.336) and rs2232365 recessive model (OR = 3.103, 95 %CI = 1.463-6.583; adjusted: OR = 3.545, 95 %CI = 1.600-7.855) were related to the severity of ischemic stroke.
FOXP3 gene rs3761548 and rs2232365 polymorphisms were risk factors for susceptibility and severity of IS.

Regulatory T (Treg) cells are indispensable in maintaining the immune homeostasis and preventing autoimmune diseases. Regulatory T (Treg) cells include thymus derived Treg cells (tTregs) and peripherally induced Treg cells (iTreg), which are differentiated from antigen stimulated CD4+ naïve T cells in presence of TGFβ. tTregs are quite stable, and more immune suppressive, while iTreg cells are less stable, and are prone to differentiate into inflammatory T cells. Therefore, identification of small molecules that could promote the differentiation of iTreg cells is an attractive strategy for autoimmune diseases. Inhibition of AKT/mTOR pathway promotes their differentiation. Whether inhibition of Lck/Fyn kinase activity (upstream of AKT/mTOR pathway) can be used to promote the differentiation of iTreg cells has not been determined. Here, we showed that Srci1, a small molecular inhibitor of Lck/Fyn, promoted the differentiation of FOXP3+ iTreg cells. Srci1 treatment resulted in inhibition of phosphorylation of key components of AKT/mTOR pathway, including mTOR, p70 S6K, 4EBP1, and promoted the expression of Foxp3 and its target genes, thereby promoted differentiation of in vitro iTreg cells. Srci1 treated iTreg cells showed more similar gene expression profile to that of tTreg cells. Our results thus suggest that inhibition of Lck/Fyn kinase activity can promote the differentiation of iTreg cells, and may have implication in autoimmune diseases.