CD4(+)CD25(+)CD127(dim/-) regulatory T cells (Tregs) have been implicated in suppressing T cell immune responses to hepatitis B virus (HBV), but the inhibition mechanism has not being clear yet. This study investigated the effects of soluble FGL2 (sFGL2) secreted by Tregs on immune suppression in chronic HBV-infected patients. We verified that sFGL2 protein and mRNA were highly expressed in Tregs. The separated Tregs by using magnetic beads from peripheral blood mononuclear cells (PBMCs) in 20 patients with chronic hepatitis B were co-cultured with PBMCs at a ratio of 1:3 with anti-CD3 stimulating antibody or FGL2 blocking antibody. The proliferation index of CD8(+)T cells after blocking FGL2 was higher than that in blank group (3.58±0.18 vs. 3.28±0.17, P=0.034) in 18 of 20 samples, and lower than that in CD3 stimulation group (3.82±0.19, P=0.026) in 16 of 20 samples. The IFN-γ secreted in the mixed culture in the absence of Tregs was higher than that in the culture in the presence of Tregs, but it could be abolished by FGL2 blocking antibody. These results suggest that sFGL2 protein secreted by Tregs suppresses the proliferation and function of CD8(+) T cells in chronic hepatitis B.
CD8-Positive T-Lymphocytes ; immunology ; metabolism ; Cells, Cultured ; Fibrinogen ; immunology ; metabolism ; Hepatitis B, Chronic ; immunology ; metabolism ; Humans ; T-Lymphocytes, Regulatory ; immunology ; metabolism

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

BACKGROUNDSystemic sclerosis (SSc) is an autoimmune disease that has three major components: inflammation, fibrosis, and vasculopathy. T-helper 17 cell (Th17) and regulatory T cell (Treg) are considered to be critical for autoimmune disease pathogenesis. The role of Th17 and Treg in SSc is still unclear. The aim of this study was to detect the presence of Th17s and CD4(+)CD25(+) Tregs in peripheral blood samples from SSc patients and to investigate the possible roles of these two T cell subsets in SSc pathogenesis.

METHODSTh17s (CD4 and IL-17 positive) and CD4(+)CD25(+) Tregs (CD4, CD25 and Foxp3 positive) in the peripheral blood mononuclear cells of 53 SSc patients and 27 healthy controls were counted by flow cytometry. The differences between SSc and control patients were analyzed. Clinical parameters, including disease duration, duration of the second symptoms, Modified Rodnan Skin Score (MRSS), anti-topoisomerase I antibody, anti-U1 ribonucleoprotein (RNP) antibody, systemic involvements, pulmonary function test (PFT) and high resolution computed tomography (HRCT) score were prospectively collected following EUSTAR (EULAR scleroderma trial and research group) protocols. The correlations between the experimental and clinical data were investigated.

RESULTSThe ratio of Th17 in SSc patients was significantly elevated compared to healthy controls (8.74% vs. 4.41%, P < 0.001). The amount of Th17 was positively correlated with disease duration (R = 0.531, P = 0.013) and duration of the second symptoms (R = 0.505, P = 0.023). The ratio of CD4(+)CD25(+) Treg in SSc patients also significantly differed from the healthy controls (3.04% vs. 2.24%, P = 0.018). Elevated Tregs were more frequently observed in patients with a high interstitial lung disease (ILD) score on computed tomography (24/36) compared with patients with normal ILD scores (4/12, P = 0.043). Elevated Tregs were also more often observed in patients with low carbon monoxide diffusing capacity (DLCO) (24/34) compared with patients with normal DLCO (4/11, P = 0.042).

CONCLUSIONST cell abnormalities are remarkable in systemic sclerosis. Th17s proliferate and their numbers increase with lengthened disease duration. Th17s might participate in both inflammation and fibrosis by secreting IL-17. CD4(+)CD25(+) Tregs also proliferate in SSc and may play important roles in promoting fibrosis.

CD4-Positive T-Lymphocytes ; metabolism ; Cells, Cultured ; Flow Cytometry ; Humans ; Interleukin-2 Receptor alpha Subunit ; metabolism ; Scleroderma, Systemic ; immunology ; metabolism ; T-Lymphocytes, Regulatory ; immunology ; metabolism ; Th17 Cells ; metabolism

Animals ; Antigens, CD ; immunology ; Cytokines ; metabolism ; Hepacivirus ; immunology ; Hepatitis C ; immunology ; prevention & control ; virology ; Hepatitis C Antibodies ; biosynthesis ; immunology ; Hepatitis C Antigens ; immunology ; Humans ; Killer Cells, Natural ; immunology ; T-Lymphocytes ; immunology ; metabolism ; T-Lymphocytes, Regulatory ; immunology ; metabolism ; Viral Proteins ; immunology

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

Asthma is a chronic disease of airway inflammation due to excessive T helper cell type 2 (Th2) response. Present treatment based on inhalation of synthetic glucocorticoids can only control Th2-driven chronic eosinophilic inflammation, but cannot change the immune tolerance of the body to external allergens. Regulatory T cells (Tregs) are the main negative regulatory cells of the immune response. Tregs play a great role in regulating allergic, autoimmune, graft-versus-host responses, and other immune responses. In this review, we will discuss the classification and biological characteristics, the established immunomodulatory mechanisms, and the characteristics of induced differentiation of Tregs. We will also discuss the progress of Tregs in the field of asthma. We believe that further studies on the regulatory mechanisms of Tregs will provide better treatments and control strategies for asthma.
Antigens, CD/analysis* ; Apyrase/analysis* ; Asthma/immunology* ; Cell Differentiation ; Cytokines/metabolism* ; Humans ; Lymphocyte Transfusion ; T-Lymphocytes, Regulatory/immunology*

PURPOSE: This study aimed to compare the regulatory T cells in cord blood of appropriate for gestational age (AGA) neonates with those of small for gestational age (SGA) neonates. MATERIALS AND METHODS: Umbilical cord blood was collected upon labor in 108 healthy full-term (between 37 and 41 gestational weeks) neonates, who were born between November 2010 and April 2012. Among them, 77 samples were obtained from AGA neonates, and 31 samples were obtained from SGA neonates. Regulatory T cells and lymphocyte subsets were determined using a flow cytometer. Student's t-test for independent samples was used to compare differences between AGA and SGA neonates. RESULTS: Regulatory T cells in cord blood were increased in the SGA group compared with normal controls (p=0.041). However, cytotoxic T cells in cord blood were significantly decreased in the SGA group compared with normal controls (p=0.007). CONCLUSION: This is the first study to compare the distribution of lymphocyte subsets including regulatory T cells in cord blood between AGA neonates and SGA neonates.
Biological Markers/metabolism ; Female ; Fetal Blood/*immunology ; Gestational Age ; Humans ; Infant, Newborn/*blood ; Infant, Small for Gestational Age/*blood ; Lymphocyte Count ; T-Lymphocytes, Cytotoxic/metabolism ; T-Lymphocytes, Regulatory/*metabolism

In a murine model of systemic lupus erythematosus (SLE)-like chronic graft-versus-host disease (cGVHD), donor CD8+T cells rapidly fall into anergy to host cells, while donor CD4+T cells hyperactivate B cells and break B-cell tolerance to self-Ags in the recipient mouse. The functional recovery of donor CD8+T cells can result in the conversion of cGVHD to acute GVHD (aGVHD), indicating that donor CD8+T-cell anergy is a restriction factor in the development of cGVHD. In this report, we present evidence that donor CD4+CD25+regulatory T cells (T(reg) cells) are critical in maintaining the donor CD8+T-cell anergy and thus suppressing the development of aGVHD in mice that are naturally prone to cGVHD. Our results provide a novel insight into the role of T(reg) cells in determining cGVHD versus aGVHD.
T-Lymphocytes, Regulatory/*immunology ; Mice, Inbred DBA ; Mice ; Interleukin-2 Receptor alpha Subunit/*metabolism ; Immune Tolerance/physiology ; Graft vs Host Disease/*immunology ; Female ; Clonal Anergy/*physiology ; Chronic Disease ; CD8-Positive T-Lymphocytes/*immunology ; CD4-Positive T-Lymphocytes/*immunology ; Animals

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