It is now established that CD4(+)CD25(+)regulatory T (Treg) cells expressing transcription factor FOXP3, a regulatory subpopulation of T cells, is indispensable for the maintenance of immunological self-tolerance and immune homeostasis. FOXP3 expression in Treg cells is specific and it is the key control factor for the development, activation and function of Treg cells. At present, CD4(+)FOXP3(+)T lymphocytes are often used to define Treg cells for scientific research. But recent studies show that human CD4(+)FOXP3(+)T cells are phenotypically and functionally heterogeneous, including suppressive and non suppressive T cells. The different functions of these cell subsets can be distinguished by phenotypic differences. This review discusses the recent research progress about phenotypic characteristics and functional heterogeneity of CD4(+)FOXP3(+)T cell subsets.
Forkhead Transcription Factors ; immunology ; Humans ; T-Lymphocytes, Regulatory ; immunology

Cytokines are secreted by various cell types and act as critical mediators in many physiological processes, including immune response and tumor progression. Cytokines production is precisely and timely regulated by multiple mechanisms at different levels, ranging from transcriptional to post-transcriptional and posttranslational processes. Monocyte chemoattractant protein-1 induced protein 1 (MCPIP1), a potent immunosuppressive protein, was first described as a transcription factor in monocytes treated with monocyte chemoattractant protein-1 (MCP-1) and subsequently found to possess intrinsic RNase and deubiquitinase activities. MCPIP1 tightly regulates cytokines expression via various functions. Furthermore, cytokines such as interleukin 1 beta (IL-1B) and MCP-1 and inflammatory cytokines inducer lipopolysaccharide (LPS) strongly induce MCPIP1 expression. Mutually regulated MCPIP1 and cytokines form a complicated network in the tumor environment. In this review, we summarize how MCPIP1 and cytokines reciprocally interact and elucidate the effect of the network formed by these components in cancer-related immunity with aim of exploring potential clinical benefits of their mutual regulation.
Chemokine CCL2/immunology* ; Humans ; Interleukin-1beta/immunology* ; Neoplasm Proteins/immunology* ; Neoplasms/pathology* ; Ribonucleases/immunology* ; Transcription Factors/immunology*

CD4(+)CD25(+) regulatory T cells are thought to be a subgroup of cells which have the function of immune suppression. 5 to 10 percentage of peripheral CD4(+) T cells and 1% - 2% of peripheral mononuclear cells are CD4(+)CD25(+) regulatory T cells in mouse or healthy human. They can suppress immune response through many pathways and sustain the stabilization of internal environment. Idiopathic thrombocytopenic purpura is a kind of autoimmunity disease which mainly has a manifestation of hemorrhage in some locations such as skin, mucosa or viscera. Recent findings support that CD4(+)CD25(+) regulatory T cells are relevant to the morbidity of idiopathic thrombocytopenic purpura. In this review, the recent advance on characteristics and function of CD4(+)CD25(+) regulatory T cells, pathogenesis of idiopathic thromocytopenic purpura and role CD4(+)CD25(+) regulatory T cells in pathogenesis of idiopathic thrombocytopenic purpura were summarized.
Forkhead Transcription Factors ; physiology ; Humans ; Purpura, Thrombocytopenic ; etiology ; immunology ; T-Lymphocytes, Regulatory ; immunology

Objective To investigate the effect of adipose mesenchymal stem cells(AMSCs) on the peripheral blood lymphocyte(PBL) in psoriasis vulgaris(PV) patients and the expression and secretion profiles of related inflammatory cytokines in the PBL.Methods AMSCs from three PV patients were co-cultured with PBL. Peripheral blood regulatory cells(Treg) and T helper cell 17(Th17)ratio was measured by flow cytometry. The anti- and pro-inflammatory cytokines expressed and secreted by PBL were detected by quantitative real-time polymerase chain reaction(qRT-PCR) and enzyme-linked immunosorbent assay(ELISA).Results The Treg/total lymphocyte ratio was significantly higher in the healthy people AMSCs+PBL co-culture group[(3.2±0.5)%;P=0.001],but AMSCs in patients had a tendency to promote the proliferation of Treg cells [(1.3±0.2)%],with no significant difference(P=0.485) when compared with the PBL culture alone group[(1.0±0.1)%]. qRT-PCR showed that the ability of PBL in expressing Treg transcription factor forkhead box p3 and transforming growth factor(TGF)-Β mRNA was significantly lower in psoriasis AMSCs+PBL co-culture group than in the healthy people AMSCs+PBL co-culture group(P=0.00,P=0.03),AMSCs had a tendency to promote the expression of interlukin(IL)-10 in peripheral blood lymphocytes,but there was no significant difference(P=0.09).ELISA showed the PBL in healthy people AMSCs+PBL co-culture group secreted the anti-inflammatory cytokine IL-10[(156.9±41.8) ng/Μl] and TGF-Β[(2774.1 ± 526.4) ng/Μl];in contrast,the abilities of PBL in PV patient AMSCs+PBL co-culture group in secreting the anti-inflammatory cytokines has a downward trend:IL-10[(90.4±28.8) ng/Μl] and TGF-Β[(1597.9±55.7) ng/Μl],although the differences were not statistically significant. After the co-culture,the proportion of Th17 cells in the psoriasis AMSCs+PBL co-culture group[(0.8±0.3)%] showed a decreasing trend when compared with the PBL culture alone group[(1.1±0.1)%],although the results were not statistically significant. Also,the proportion of Th17 cells showed no significant difference between PV patient AMSCs+PBL co-culture group and healthy people AMSCs+PBL co-culture group. Finally,both the psoriasis AMSCs+PBL co-culture group and the healthy people AMSCs+PBL co-culture group showed no obvious inhibitory effect on the expression and secretion of Th17 transcription factor retinoid-related orphan nuclear receptor Γt and pro-inflammatory cytokines IL-17 and IL-23 in PBL,and there was no significant difference between these two groups.Conclusions AMSCs in PV patients have decreased ability in regulating the anti-inflammatory function of peripheral blood Treg lymphocytes. However,they have no effect on the proinflammatory effect of peripheral blood Th17 lymphocytes.
Adipose Tissue ; cytology ; Cytokines ; immunology ; Forkhead Transcription Factors ; immunology ; Humans ; Inflammation ; immunology ; Mesenchymal Stem Cells ; cytology ; Psoriasis ; immunology ; T-Lymphocytes, Regulatory ; immunology ; Th17 Cells ; immunology

BACKGROUNDRecent studies have shown that T helper type-2 (Th2) cells can induce the apoptosis of CD4+CD25+ Treg cells or resist the immunosuppressive effect of Treg cells. We hypothesize that an imbalance of Th2/Treg is present in patients with allergic asthma.

METHODSTwenty-two patients with mild asthma, 17 patients with moderate to severe asthma, and 20 healthy donors were enrolled. All patients were allergic to house dust mites. The proportion of peripheral blood CD4+CD25+ Treg cells and Th2 cells were determined by flow cytometry. The concentration of interleukin (IL)-10, transforming growth factor (TGF)-β and IL-4 in plasma was determined by enzyme linked immunosorbent assay. In these subjects, peripheral blood mononuclear cells from 17 mild asthmatic patients, 13 moderate to severe asthmatic patients and 14 healthy donors were acquired and expression of forkhead box P3 (Foxp3) and GATA-3 mRNA was detected by reverse-transcriptase polymerase chain reaction.

RESULTSCompared with healthy donors and patients with mild asthma, the percent of CD4+CD25+ Treg cells and plasma IL-10 levels were decreased in patients with moderate to severe asthma. There were no significant differences in Foxp3 mRNA expression among three groups, but a downward trend seen among patients with asthma. However, the percent of Th2 cells, IL-4 levels and expression of GATA-3 mRNA was markedly higher in patients with mild and moderate to severe asthma than in the control group. The ratio of Th2/Treg and their cytokines was increased in allergic asthma, especially for moderate to severe asthma. The ratio of GATA-3/Foxp3 mRNA was also increased in allergic asthma. In patients with moderate to severe asthma, the percentage of peripheral blood Treg cells was negatively correlated to the percentage of Th2 cells and IL-4 levels.

CONCLUSIONSThe decline of CD4+CD25+ Treg cells in patients with moderate to severe asthma may play an important role in progress of the disease. Furthermore, the deficiency of CD4+CD25+ Treg cells was associated with the over-expression of Th2 response.

Asthma ; etiology ; immunology ; Cytokines ; blood ; Forkhead Transcription Factors ; genetics ; GATA3 Transcription Factor ; genetics ; Humans ; RNA, Messenger ; analysis ; T-Lymphocytes, Regulatory ; immunology ; Th2 Cells ; immunology

OBJECTIVETo review the current research into Foxp3(+) regulatory T cells (Treg) cell surface molecules, plasticity of Treg cells and mechanisms of Treg cell suppression and to explore the possibilities to interfere in Treg cell suppression of anti-tumor immunity.

DATA SOURCESA literature search of all English articles was performed on the online electronic PubMed database dated 1995 to 2010. The keywords searched included: CD4(+)CD25(+)Foxp3(+) regulatory T lymphocytes, cancer, and immunotherapy. After finding relevant articles within these search limits, a manual search was conducted through the references from these articles.

STUDY SELECTIONArticles regarding the role of Treg cells in tumor immunity and the utility of Treg cells in tumor immunotherapy.

RESULTSThe results show that significant numbers of Treg cells are found in many tumors and it has been shown that the number of tumor infiltrating Treg cells correlates with adverse clinic outcomes. Treg cells are emerging as a key component of acquired tolerance to tumors.

CONCLUSIONSSeveral mechanisms of immunosuppression can be mediated by Treg cell function. Distinct immunosuppressive molecules expressed by Treg cells or diverse molecules related to Treg induction or migration represent potential drug targets for cancer immunotherapy.

Forkhead Transcription Factors ; metabolism ; Humans ; Immunosuppression ; methods ; Immunotherapy ; methods ; Neoplasms ; immunology ; therapy ; T-Lymphocytes, Regulatory ; metabolism

Mammalian target of rapamycin complex 2 (mTORC2) is a key downstream mediator of phosphoinositol-3-kinase (PI3K) dependent growth factor signaling. In lymphocytes, mTORC2 has emerged as an important regulator of cell development, homeostasis and immune responses. However, our current understanding of mTORC2 functions and the molecular mechanisms regulating mTORC2 signaling in B and T cells are still largely incomplete. Recent studies have begun to shed light on this important pathway. We have previously reported that mTORC2 mediates growth factor dependent phosphorylation of Akt and facilitates Akt dependent phosphorylation and inactivation of transcription factors FoxO1 and FoxO3a. We have recently explored the functions of mTORC2 in B cells and show that mTORC2 plays a key role in regulating survival and immunoglobulin (Ig) gene recombination of bone marrow B cells through an Akt2-FoxO1 dependent mechanism. Ig recombination is suppressed in proliferating B cells to ensure that DNA double strand breaks are not generated in actively dividing cells. Our results raise the possibility that genetic or pharmacologic inhibition of mTORC2 may promote B cell tumor development as a result of inefficient suppression of Ig recombination in dividing B cells. We also propose a novel strategy to treat cancers based on our recent discovery that mTORC2 regulates Akt protein stability.
B-Lymphocytes ; cytology ; immunology ; Cell Differentiation ; Cell Transformation, Neoplastic ; Humans ; Transcription Factors ; metabolism

CD4+ T lymphocytes play a major role in regulation of adaptive immunity. Upon activation, naive T cells differentiate into different functional subsets. In addition to the classical Th1 and Th2 cells, several novel effector T cell subsets have been recently identified, including Th17 cells. There has been rapid progress in characterizing the development and function of Th17 cells. Here I summarize and discuss on the genetic controls of their differentiation and emerging evidence on their plasticity. This information may benefit understanding and treating immune diseases.
Animals ; CD4-Positive T-Lymphocytes/cytology/*immunology ; Cell Differentiation ; Cell Lineage ; Cytokines/*genetics ; Epigenesis, Genetic ; Gene Expression Regulation ; Humans ; Interleukin-17/immunology/metabolism ; T-Lymphocytes, Regulatory ; Th1 Cells/immunology ; Th17 Cells/*immunology ; Th2 Cells/immunology ; Transcription Factors/*genetics ; Transcription, Genetic

Adaptation of the maternal immune response to accommodate the semi-allogeneic fetus is necessary for pregnancy success, and disturbances in maternal tolerance are implicated in miscarriage. FOXP3, a member of the X chromosome-encoded forkhead transcription factor family, is indispensable for the differentiation of regulatory T cells. Regulatory T cells (CD4+ CD25+ FOXP3+ Treg) are pivotal to the maintenance of self-tolerance and the control of immune homeostasis. Many studies show that CD4+ CD25+ FOXP3+ Treg cells are essential for maternal tolerance of the conceptus. Treg cells accumulate in the decidua and are elevated in maternal blood from early in the first trimester. Inadequate expression of FOXP3 is associated with recurrent spontaneous abortion, unexplained infertility and recurrent implantation failure. CD4+ CD25+ FOXP3+ Treg cells offer an attractive target for treatment of auto-immune disease and allograft tolerance and might become a powerful new tool for the treatment of fertility pathologies stemming from disturbances in immune tolerance. This paper reviews the structure, function, expression regulation of FOXP3 and its relation with reproduction.
Abortion, Habitual ; etiology ; Female ; Forkhead Transcription Factors ; metabolism ; Humans ; Immune Tolerance ; Pregnancy ; immunology ; T-Lymphocytes, Regulatory ; immunology

PURPOSE: Forkhead box p3 (Foxp3) positive T regulatory cells (Tregs) have a functionally immunosuppressive property that prevents effector cells from acting against self in autoimmune diseases or a tumor. It is known that Tregs may be highly relevant in cancer progression. Dendritic cells (DCs) induce cutaneous immune response, however several studies have suggested that DCs are involved in immunosuppression. The aim of this study is to evaluate the prevalence of Tregs and DCs infiltration in cutaneous premalignant and malignant squamous lesions. MATERIALS AND METHODS: We evaluated Tregs and DCs in skin tissue samples obtained from 83 patients with actinic keratosis, Bowen's disease or squamous cell carcinoma by immunohistochemistry. RESULTS: The prevalence of Tregs and DCs was significantly higher in squamous cell carcinoma and Bowen's disease than in actinic keratosis. In addition, the number of DCs was closely correlated with the prevalence of Tregs, and DCs were also located in direct proximity to Tregs. CONCLUSION: Tregs is related to cutaneous squamous tumor progression.
Bowen's Disease/immunology/metabolism/pathology ; Carcinoma, Squamous Cell/immunology/metabolism/pathology ; Dendritic Cells/immunology/metabolism/pathology ; Forkhead Transcription Factors/immunology/*metabolism ; Humans ; Immune Tolerance ; Keratosis, Actinic/immunology/metabolism/pathology ; Skin Neoplasms/*immunology/metabolism/pathology ; T-Lymphocytes, Regulatory/*immunology/metabolism/pathology