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

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

OBJECTIVETo investigate the dynamic changes in CD4(+)CD25(+) regulatory T cells and Foxp3 expression in peripheral blood and brain tissues of rats after acute cerebral ischemia and explore their role in the pathophysiological evolution of acute ischemic stroke.

METHODSForty-eight Wistar rats were randomized equally into ischemia and sham-operated groups, and right middle cerebral artery occlusion was induced in the former group. Flow cytometry and immunohistochemistry were employed to detect CD4(+)CD25(+) T cells and Foxp3 expression, respectively, in the peripheral blood and brain tissue at 1, 3, 7, and 14 days after modeling. The behavioral changes of the rats were evaluated using an improved NSS neurological functional scoring system.

RESULTSThe neurological function scores of the two groups both gradually declined after the operation, and showed significant differences between the two groups at all the time points of measurement (P<0.01). The CD4(+)CD25 T cells in the peripheral blood were similar between the two group at 1 and 3 days after the operation (P>0.05), but increased significantly in the ischemia group at 7 and 14 days (P<0.05) with an inverse correlation to the neurological scores (r=-0.68, P=0.01). Immunohistochemistry detected the presence of Foxp3 primarily in the ischemic region of the brain tissue 1 day after cerebral ischemia; the contralateral hemisphere also showed a small quantity of Foxp3 expression. No Foxp3 expression was detected in the brain tissue of the sham-operated group.

CONCLUSIONCD4(+)CD25 T regulatory cells participate in the inflammatory immune reactions as early as 1 day after acute cerebral ischemia in rats, which might be a protective mechanism of the brain cells.

Animals ; Brain ; metabolism ; Brain Ischemia ; immunology ; metabolism ; Forkhead Transcription Factors ; immunology ; metabolism ; Male ; Rats ; Rats, Wistar ; T-Lymphocytes, Regulatory ; immunology ; metabolism

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

Child ; Child, Preschool ; Female ; Forkhead Transcription Factors ; genetics ; metabolism ; Humans ; Immune System Diseases ; immunology ; Male ; Purpura, Thrombocytopenic, Idiopathic ; genetics ; immunology ; metabolism ; T-Lymphocytes, Regulatory ; immunology

Objective To explore the expression patterns of immune negative regulator FoxP3+Treg and PD-L1 protein in cervical carcinoma and its precancerous lesions. Methods The expression patterns of FoxP3+Treg and PD-L1 protein in 45 cases of cervical lesions tissues of the cervix and 20 cases of normal cervix tissues by using immunohistochemistry (IHC). Results Compared with the normal cervix,the expressions of FoxP3+Treg (H=43.211,P=0.000) and PD-L1 protein (t=213.00,P=0.001) were significantly increased in cervical lesions. Compared with the low-grade squamous cell carcinoma,the invasiveness of FoxP3+Treg was increased in high-grade squamous cell carcinoma (H=28.307,P=0.000),along with increased expression of PD-L1 protein (t=239.000,P=0.028). The FoxP3+Treg expression was positively correlated with PD-L1 protein expression in abnormally differentiated cells (r=0.364,P=0.003). Conclusion Along with the progression of cervical cancer,the FoxP3+Treg amount increases in the local microenvironment,along with enhanced PD-L1 protein expression in abnormally differentiated cells.
B7-H1 Antigen ; metabolism ; Carcinoma, Squamous Cell ; Female ; Forkhead Transcription Factors ; metabolism ; Humans ; Immunohistochemistry ; T-Lymphocytes, Regulatory ; immunology ; Tumor Microenvironment ; immunology ; Uterine Cervical Neoplasms ; immunology

BACKGROUNDTraumatic brain injury (TBI) is a life-threatening disease worldwide. Regulatory T cells (Treg cells) were involved in the immunological system in central nervous system. It is defined as a subpopulation of CD4 + cells that express CD25 and transcription factor forkhead box P3. The level of circulating Treg cells increases in a variety of pathologic conditions. The purpose of this study was to uncover the role of circulating Treg cells in TBI.

METHODSA clinical study was conducted in two neurosurgical intensive care units of Tianjin Medical University General Hospital and Second Hospital of Tianjin Medical University (Tianjin, China). Forty patients and 30 healthy controls were recruited from August 2013 to November 2013. Circulating Treg cells was detected on the follow-up period of 1, 4, 7, 14, and 21 days after TBI. Blood sample (1 ml) was withdrawn in the morning and processed within 2 h.

RESULTSThere was no significant difference in the level of circulating Treg cells between TBI patients and normal controls during follow-up. TBI patients exhibited higher circulating Treg level than normal controls on the 1 st day after TBI. Treg level was decreased on the 4 th day, climbed up on the 7 th day and peaked on 14 th day after TBI. Treg cells declined to the normal level on 21 th day after TBI. The level of circulating Treg cells was significantly higher in survival TBI patients when compared to nonsurvival TBI patients. TBI patients with improved conditions exhibited significantly higher circulating Treg level when compared to those with deteriorated conditions. The circulating Treg level was correlated with neurologic recovery after TBI. A better neural recovery and lower hospital mortality were found in TBI patients with circulating Treg cells more than 4.91% in total CD4 + mononuclear cells as compared to those with circulating Treg cells less than 4.91% in total CD4 + mononuclear cells in the first 14 days.

CONCLUSIONSThe level of circulating Treg cells is positively correlated with clinical outcome of TBI. The level of Treg cells predicts the progress for TBI patients and may be a target in TBI treatment.

Adult ; Brain Injuries ; immunology ; CD4 Antigens ; metabolism ; Female ; Flow Cytometry ; Forkhead Transcription Factors ; metabolism ; Humans ; Interleukin-2 Receptor alpha Subunit ; metabolism ; Male ; Middle Aged ; T-Lymphocytes, Regulatory ; metabolism

OBJECTIVE: To investigate the expression levels of Th9, Th17 and Treg cells in peripheral blood of patients with chronic rhinosinusitis with nasal polyps (CRSwNP), and explore the role of Th9, Th17 and Treg cells in the progression of CRSwNP. METHOD: Forty-six cases with CRSwNP served as an experimental group, while 22 cases with simple nasal bleeding or nasal septum deviation served as a control group. The peripheral blood of patients in both groups was collected and analyzed. (1) Using flow cytometry (FCM) to detect the expression rates of Th9, Th17 and Treg cells in peripheral blood. (2) Using qRT-PCR to detect the expression of relevant transcription factor of Th9, Th17 and Treg cells (IL-9mRNA, PU. 1, IRF-4, RoRc, and Foxp3). (3) Using SPSS16.0 to analyse the differentiations and the revelance among these three cells. RESULT: (1) The expression rates of Th9 and Th17 cells in patients with CRSwNP (1.29% ± 0.18%, 4.03% ± 0.69%) was higher than the control group (0.45% ± 0.14%, 1.35% ± 0.26%). But the expression rates of Treg cells in the experimental group (2.98% ± 0.13%) was significantly lower than the control group (5.44% ± 0.57%). The differences were statistically significant (P < 0.05). (2) The expression of revelant transcription factor (IL-9mRNA, PU.1, IRF-4, RoRc) in NP group was also higher than the control group. The expression of Foxp3 in the control group was higher than NP, the differences both were statistically significant (P < 0.05). (3) The difference between Th9 and Th17 in patients with NP was not significant (P > 0.05), and the negative correlation was found between Th17 and Treg (r = -0.549, P < 0.05). CONCLUSION The high expression level of Th9 and Th17 cells might promote the development of NP, whereas the low expression level of Treg cells might further aggravate the occurrence of NP. The main function of the imbalance of Th17/Treg cells may be immune regulation in the pathogenesis of nasal polys.
Case-Control Studies ; Cell Differentiation ; Disease Progression ; Epistaxis ; Flow Cytometry ; Forkhead Transcription Factors ; metabolism ; Humans ; Nasal Polyps ; immunology ; pathology ; Nasal Septum ; abnormalities ; Rhinitis ; immunology ; pathology ; Sinusitis ; immunology ; pathology ; T-Lymphocytes, Regulatory ; cytology ; Th17 Cells ; cytology ; Transcription Factors ; metabolism

BACKGROUNDDendritic cells (DCs) can recognize the pathogen-associated molecular patterns (PAMP) of Aspergillus fumigatus (A. fumigatus), activating the immune response. During A. fumigatus infection, a Th and Treg response induced in the fungi-pulsed DCs is not yet well understood.

METHODSIn this study, bone marrow-derived dendritic cells (BMDCs) were separated and proliferated from C57BL/6 mice. A. fumigatus pulsed DCs were generated and cultured with CD4(+) T cells derived from the spleen of C57BL/6 mice in vitro. CD4(+) T cells differentiation after co-culture were analyzed by flow cytometry, ELISA, and real-time PCR analysis.

RESULTSThe A. fumigatus pulsed DCs exhibited increased Th1 and Treg frequency, Th1-related cytokines (IFN-γ and IL-12), Treg-related cytokines (TGF-β) and T-bet, and Foxp3 mRNA levels compared with the control group. There was no significant difference between A. fumigatus pulsed DCs group and the control group about Th17 and Th2 frequency.

CONCLUSIONSThe inactivated conidia of A. fumigatus were able to activate BMDCs and made them capable of triggering T cell responses in vitro. A. fumigatus loaded DCs was a weak inducer of Th17 and Th2, but induced a strong Th1 and Treg response.

Animals ; Aspergillus fumigatus ; pathogenicity ; Cytokines ; metabolism ; Dendritic Cells ; immunology ; microbiology ; Forkhead Transcription Factors ; metabolism ; Interleukin-12 ; metabolism ; Male ; Mice ; Mice, Inbred C57BL ; T-Lymphocytes, Helper-Inducer ; immunology ; T-Lymphocytes, Regulatory ; immunology ; Th1 Cells ; immunology ; Transforming Growth Factor beta ; metabolism

OBJECTIVETo investigate the Th17 cell and Treg cell levels in patients with sarcoidosis, and their relation to disease activation and glucocorticoids treatment.

METHODSTwenty-three sarcoidosis patients admitted in Yinzhou People's Hospital from January 2009 to December 2013 and 25 healthy subjects (controls) were included in this study. The blood samples and bronchoalveolar lavage fluid (BALF) samples were collected in all patients before and after glucocorticoids treatment. The serum angiotensin converting enzyme (SACE) levels were detected. The percentages of Th17 cells and Treg cells in peripheral blood and BALF were determined by flow cytometry, the concentrations of cytokines in serum and supernatants of BALF were measured by enzyme-linked immunosorbent assay (ELISA). The levels of ROR-γt and Foxp3 mRNA transcripts in peripheral blood mononuclear cells (PBMC) were determined by real-time quantitative PCR. The potential correlation between the percentages of Th17 or Treg cells and SACE levels was evaluated.

RESULTSCompared with healthy controls, significantly higher frequencies of Th17 cells (4.34%±0.89% vs 1.60% ± 0.42%), lower frequencies of Treg cells (1.28% ± 0.37% vs 3.39% ± 0.50%) in peripheral blood were observed. Higher level of ROR-γt mRNA (21.31 ± 3.55 vs 3.63 ± 1.00) and lower level of Foxp3 mRNA (1.60 ± 0.24 vs 3.12 ± 0.76) in peripheral blood were detected in sarcoidosis patients in active stage (before glucocorticoids treatment) (all P<0.01). After the treatment of glucocorticoids, these index in peripheral blood were significantly improved (Th17 cells 2.16% ± 0.68%，Treg cells 2.21% ± 0.42%, ROR-γt mRNA 10.15 ± 1.93, Foxp3 mRNA 2.44 ± 0.38) ( all P<0.05). The changing trends of Th17 and Treg cell cytokines levels in serum were consistent with two type cells. Meanwhile, the changing trends of above index in BALF of patients treated by glucocorticoids were consistent with those in sarcoidosis patients in active stage. The increased ratios of Th17 cells to Treg cells were positively correlated with the level of serum SACE (r= 0.781).

CONCLUSIONThe imbalance of Th17 cells and Treg cells in peripheral blood and airway may be involved in the pathogenesis of sarcoidosis, which was associated with the activity of disease, and the treatment of glucocorticoids may achieve a therapeutic effect by correcting the immune imbalance.

Bronchoalveolar Lavage Fluid ; Case-Control Studies ; Cytokines ; immunology ; Enzyme-Linked Immunosorbent Assay ; Forkhead Transcription Factors ; metabolism ; Humans ; Leukocytes, Mononuclear ; metabolism ; Nuclear Receptor Subfamily 1, Group F, Member 3 ; metabolism ; Sarcoidosis ; immunology ; T-Lymphocytes, Regulatory ; immunology ; Th17 Cells ; immunology