Naturally occurred CD4(+)CD25(+) regulatory T cells derived from thymus. It plays an important role in self-tolerance and allograft-tolerance through cell-contact dependent mechanism. This review described the advances of study on the probable regulatory factors of the naturally occurring regulatory T cells, such as Foxp3, IL-2, TGF-beta(1), dendritic cells and CTLA-4. As a marker of Treg, the expression of Foxp3 could be used to identify regulatory T cells. The combination of interferon 2 and IL-2Ralpha would activate Treg and promote its proliferation through the phosphorylation of STAT5. TGF-beta(1) on the cell surface may influence the function of Treg, while the secretion type of TGF-beta may promote the proliferation of Treg. Dendritic cells can positively or negatively regulate Treg, which depends on the signal transduction pathway. CTLA-4 expressed on the surface of Treg might bind to the B7 molecule on the DC, effective cell or Treg itself directly or indirectly regulate Treg.
Animals ; CD4 Antigens ; metabolism ; Cell Differentiation ; immunology ; Cells, Cultured ; Dendritic Cells ; immunology ; Forkhead Transcription Factors ; physiology ; Humans ; Interleukin-2 ; physiology ; Interleukin-2 Receptor alpha Subunit ; metabolism ; T-Lymphocytes, Regulatory ; cytology ; immunology ; metabolism ; Thymus Gland ; cytology ; Transforming Growth Factor beta ; physiology

BACKGROUND: While a significant genetic predisposition to schizophrenia has been proposed, the mode of inheritance or nature of etiological factors is unknown. Previous reports of a genome-wide survey for schizophrenia susceptibility genes have indicated a possible region of linkage on chromosome 22. In order to test the possibility that the interleukin-2 recepto beta chain(IL-2R beta ) gene on chromosome 22 is of etiological importance in schizophrenia, a case-control association study was conducted. METHODS: Subjects were ninety-three schizophrenic patients with a diagnosis of schizophrenia by DSM- III -R criteria and ninety-seven normal controls. Schizophrenic patients were divided by clinical phenotypes such as DSM- III -R diagnostic subtypes, positive and negative symptoms, and family history so as to increase the homogeneity of schizophrenics. Genomic DNA was extracted from whole blood lymphocytes according to standard procedures. The DNA was used to study a dinucleotide repeat in the IL-2R beta gene. To reveal the dinucleotide polymorphism, genomic DNA of subjects was amplified by polymerase chain reactions(PCR). RESULTS: At the IL-2R beta gene locus, all the previously reported alleles (eight different alleles) of a dinucleotide polymorphism were identified. There was no significant difference between number of heterozygosity in schizophrenic patients and in normal controls. There was no significant difference in the distribution of frequencies of alleles between schizophrenics and normal controls. In addition, there was no significant difrfrence in the allele frequencies among subtypes of schizophrenic patients according to DSM- III -R diagnostic subtypes, positive and negative symptoms, and family history. CONCLUSIONS: The present study did not detect a difference in frequencies of alleles of a dinucleotide polymorphism at the IL-2R beta gene locus between schizophrenic patients and normal controls. These results do not support an evidence that IL-2R beta gene plays, a major role in the etiology of schizophrenia.
Alleles ; Case-Control Studies ; Chromosomes, Human, Pair 22* ; Diagnosis ; Dinucleotide Repeats ; DNA ; Gene Frequency ; Genetic Predisposition to Disease ; Humans ; Interleukin-2 Receptor beta Subunit ; Interleukin-2* ; Lymphocytes ; Phenotype ; Schizophrenia ; Wills

The study was purposed to investigate the immune regulatory effects of human bone marrow mesenchymal stem cells (hMSCs) on Foxp3 expressing CD4(+)CD25(+) regulatory T cells and to explore the mechanism of immune modulation by hMSCs. Human MSCs were isolated and expanded from bone marrow cells, and identified with cell morphology, and the phenotypes were assessed by immunohistochemistry. Human peripheral blood mononuclear cells (hPBMNCs) were prepared by centrifugation on a Ficoll Hypaque density gradient. The hMSCs (1 x 10(3), 1 x 10(4), 1 x 10(5)) were added into wells containing hPBMNCs (1 x 10(6)) from an unrelated donor in the presence of rhIL-2. After 5 days of co-culture, the percentage of CD4(+)CD25(+) T cells was detected by flow cytometry. T cell proliferation was assessed by [(3)H] thymidine incorporation using a liquid scintillation counter. The expression of Foxp3 in CD4(+)CD25(+) T cells was detected by reverse transcription polymerase chain reaction (RT-PCR). Cytokines (TGF-beta, IL-12, IFN-gamma, IL-10) concertrations of cultured supernatants were measured with ELISA. The results indicated that in all the experiments, the presence of hMSCs with hPBMNCs resulted in a statistically significant decrease in T cell proliferation, in dose-dependent manner. The increase of percentage of CD4(+)CD25(+) T cells in the peripheral CD4(+) T cell was observed after coculturing lymphocytes with hMSCs (p < 0.01). The expression of Foxp3-mRNA (Foxp3/beta-actin) in hMSCs groups was significantly higher than that in the control and was negatively associated with the value of CPM representing T proliferation. The levels of TGF-beta and IL-10 were higher in hMSCs groups than that in the control, and the levels of TGF-beta and IL-10 correlated positively with Foxp3-mRNA expression and the percentage of CD4(+)CD25(+) T cells. However, the secretion of IL-12 and IFN-gamma was significantly attenuated by hMSCs coculture, and there was no correlation with Foxp3-mRNA expression and the percentage of CD4(+)CD25(+) T cells. It is concluded that the Foxp3 expressing regulatory T cells may play an important role in the immune regulatory by hMSCs. Its mechanism is related to that the hMSCs-mediated TGF-beta and IL-10 convert CD4(+)CD25(-) T cells into CD4(+)CD25(+) T regulatory T cells, which specifically inhibits the proliferation of T cells.
Bone Marrow Cells ; cytology ; Cell Proliferation ; Cells, Cultured ; Coculture Techniques ; Forkhead Transcription Factors ; metabolism ; Humans ; Immunization ; Interleukin-10 ; biosynthesis ; Interleukin-2 Receptor alpha Subunit ; immunology ; metabolism ; Mesenchymal Stromal Cells ; cytology ; T-Lymphocytes, Regulatory ; immunology ; metabolism ; Transforming Growth Factor beta ; biosynthesis

OBJECTIVETo evaluate the changes of CD(4)(+)CD(25)(+) T cells in peripheral blood from patients with breast cancer.

METHODSSixty four patients with breast cancer, 15 patients with benign breast tumors and 9 healthy volunteers were included in this study. The proportion of CD(4)(+)CD(25)(+) T cells population in total T cells was evaluated by flow cytometric analysis. The cytokine production (TGF-beta1) was measured by ELISA.

RESULTSThe population of CD(4)(+)CD(25)(+) T cells in peripheral blood from patients with breast cancer accounted for (5.1 +/- 2.9)% of the total amount of T lymphocytes, and was significantly higher in comparison with that in patients with benign tumors and in healthy volunteers (P < 0.05). The CD(4)(+)CD(25)(+) T cells population in breast cancer patients was positively correlated with the cancer size and with TGF-beta1 level (r = 0.511 and r = 0.253, respectively), and negatively correlated with CD(8)(+)CD(28)(+) T cells and NK cells (r = -0.243 and r = -0.301, respectively).

CONCLUSIONThe CD(4)(+)CD(25)(+) regulatory T cells in peripheral blood of patients with breast cancer is significantly increased in comparison with that in patients with benign breast tumor and in healthy subjects. It may be responsible for immune suppression in breast cancer patients.

Adult ; Aged ; Breast Neoplasms ; immunology ; CD4-Positive T-Lymphocytes ; immunology ; Cell Count ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Interleukin-2 Receptor alpha Subunit ; immunology ; Middle Aged ; T-Lymphocyte Subsets ; immunology ; Transforming Growth Factor beta ; biosynthesis ; genetics

BACKGROUND: Astrocytes are the major glial cells involved with the chemical homeostasis and mechanical supports of central nervous system. Recently, astrocytes were found to actively synthesize and secrete many immunologically active cytokines and express receptors for these mediators, which proposed their autocrine and paracrine roles in the pathogenesis of many neurodegenerative or autoimmune diseases, I.e., multiple sclerosis, Alzheimer's disease, etc. The identification of various chemical mediators secreted by astrocytes and receptors expressed on astrocytes seems to be crucial for understanding their pathogenetic roles in these diseases. Our investigation was conducted to test the expression of interleukin-2 receptor alpha Subunit (IL-2Ralpha) on primary cultured astrocytes, which has not been studied yet. METHODS: Astrocytes were obtained from the surgical specimen of a patient with intractable temporal lobe epilepsy. Neuropathological examination of the specimen revealed hippocampal sclerosis only with normal lateral temporal neocortex from which cultured astrocytes were obtained. All experiments were performed within 2 months after starting primary culture. Cultured astrocytes were incubated with IL-1, IL-2, IL-6, TGF-beta And TNF-alpha For 24 hours. RT-PCR was performed to investigate the transcription of IL-2R. RESULTS: RT-PCRs for the IL-2Ralpha Showed constitutional expression on the adult cultured astrocytes, which was increased by IL-1, IL-2, IL-6 and TNF-alpha But decreased by treatment of TGF-beta. CONCLUSIONS: Adult astrocytes expressed IL-2Ralpha Constitutively, which were upregulated by IL-1, IL-2, IL-6 and TNF-alpha. These findings suggest the immunocompetence of astrocytes, which may be important in the pathogenesis of many neurological diseases.
Adult* ; Alternative Splicing ; Alzheimer Disease ; Astrocytes* ; Autoimmune Diseases ; Central Nervous System ; Cytokines ; Epilepsy, Temporal Lobe ; Homeostasis ; Humans ; Humans* ; Immunocompetence ; Interleukin-1 ; Interleukin-2 Receptor alpha Subunit ; Interleukin-2* ; Interleukin-6 ; Multiple Sclerosis ; Neocortex ; Neuroglia ; RNA, Messenger ; Sclerosis ; Transforming Growth Factor beta ; Tumor Necrosis Factor-alpha

IL-4 and IL-13 are closely related cytokines that are produced by Th2 cells. However, IL-4 and IL-13 have different effects on the development of asthma phenotypes. Here, we evaluated downstream molecular mechanisms involved in the development of Th2 type asthma phenotypes. A murine model of Th2 asthma was used that involved intraperitoneal sensitization with an allergen (ovalbumin) plus alum and then challenge with ovalbumin alone. Asthma phenotypes, including airway-hyperresponsiveness (AHR), lung inflammation, and immunologic parameters were evaluated after allergen challenge in mice deficient in candidate genes. The present study showed that methacholine AHR and lung inflammation developed in allergen-challenged IL-4-deficient mice but not in allergen-challenged IL-13-deficient mice. In addition, the production of OVA-specific IgG2a and IFN-gamma-inducible protein (IP)-10 was also impaired in the absence of IL-13, but not of IL-4. Lung-targeted IFN-gamma over-expression in the airways enhanced methacholine AHR and non-eosinophilic inflammation; in addition, these asthma phenotypes were impaired in allergen-challenged IFN-gamma-deficient mice. Moreover, AHR, non-eosinophilic inflammation, and IFN-gamma expression were impaired in allergen-challenged IL-12Rbeta2- and STAT4-deficient mice; however, AHR and non-eosinophilic inflammation were not impaired in allergen-challenged IL-4Ralpha-deficient mice, and these phenomena were accompanied by the enhanced expression of IL-12 and IFN-gamma. The present data suggest that IL-13-mediated asthma phenotypes, such as AHR and non-eosinophilic inflammation, in the Th2 type asthma are dependent on the IL-12-STAT4-IFN-gamma axis, and that these asthma phenotypes are independent of IL-4Ralpha-mediated signaling.
Allergens/immunology ; Animals ; Asthma/complications/*immunology/pathology/physiopathology ; Bronchial Hyperreactivity/complications/immunology/pathology ; Disease Models, Animal ; Interferon-gamma/*immunology ; Interleukin-12/*immunology ; Interleukin-12 Receptor beta 2 Subunit/metabolism ; Interleukin-13/deficiency/*immunology ; Interleukin-4/deficiency ; Methacholine Chloride ; Mice ; Mice, Transgenic ; Models, Immunological ; Organ Specificity ; Pneumonia/complications/immunology/pathology ; Receptors, Cell Surface/metabolism ; STAT4 Transcription Factor/*metabolism ; Signal Transduction/*immunology ; Th2 Cells/*immunology

OBJECTIVETo investigate whether the CD4+CD25+Foxp3+ regulatory T cells are associated with serum TGF beta 1 in patients with hepatitis B.

METHODSPatients with chronic hepatitis B (CHB), chronic asymptomatic carriers (AsC), normal subjects (NS) and the resolved from HBV infection (Resolved) were recruited in this study. Flow cytometric analysis was used to detect the frequency and phenotype of peripheral CD4+CD25+Foxp3+ T cells, and Foxp3 gene expression were examined by real time PCR. Serum TGF beta 1 levels were measured by ELISA (enzyme-linked immunosorbent assay).

RESULTSPatients with CHB or AsC exhibited significantly higher frequency of CD4+CD25+Foxp3+ T cells compared to healthy controls. CD4+CD25+ T cells derived from patients with CHB and AsC expressed higher level of Foxp3-mRNA. Furthermore, the frequency of CD4+CD25+Foxp3+ regulatory T cells was correlated with serum HBV DNA copy numbers in patients with CHB and AsC. Our results indicated that the serum TGF beta was increased in CHB and AsC patients compared to control patients, and that serum TGF beta was correlated with the expression of Foxp3-mRNA and the frequency of CD4+CD25+Foxp3+ regulatory T cells in patients with CHB and AsC.

CONCLUSIONSThe findings have important implication in the understanding of the role and mechanism of aberrant CD4+CD25+Foxp3+ regulatory T cells in the maintenance of chronicity in hepatitis B patients.

Adolescent ; Adult ; CD4 Antigens ; immunology ; metabolism ; Carrier State ; blood ; immunology ; Female ; Flow Cytometry ; Forkhead Transcription Factors ; immunology ; metabolism ; Hepatitis B Surface Antigens ; blood ; immunology ; Hepatitis B, Chronic ; blood ; immunology ; Humans ; Interleukin-2 Receptor alpha Subunit ; immunology ; metabolism ; Male ; Phenotype ; Polymerase Chain Reaction ; RNA, Messenger ; genetics ; metabolism ; T-Lymphocytes, Regulatory ; immunology ; virology ; Transforming Growth Factor beta ; blood ; Viral Load ; Young Adult

The study was aimed to investigate the effect of anti-mouse CD122 antibody on the hematopoietic repopulating capacity of cord blood CD34⁺ cells in a humanized murine model-non obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. After sublethal irradiation with γ-ray, NOD/SCID mice were intraperitoneally injected with 200 µg mouse isotype control antibody or anti-mouse CD122 antibody. Human cord blood CD34⁺ cells or phosphate-buffered saline (PBS) were injected via the tail vein at 6-8 hours later. Cohort of the mice injected with anti-mice CD122 antibody or control antibody alone were sacrificed at different time point (at week 2, 3, and 4 weeks) after the injection, and the percentage of NK cells in the peripheral blood was analyzed by flow cytometry. To evaluate the effect of anti-mouse CD122 antibody on the repopulating capacity of cord blood CD34⁺ cells in the recipient mice, phenotype analysis was performed in the bone marrow at 6 and 8 weeks after the transplantation. The results showed that the proportion of NK cells in the peripheral blood were (4.6 ± 0.6)% and (5.7 ± 1.7)% at week 2 and 3 after anti-CD122 antibody injection respectively,which decreased by 60%, compared with the mice injected with isotype control antibody. After 6 and 8 weeks of cord blood CD34⁺ cell transplantation,the percentage of human CD45⁺ in the bone marrow of the recipient mice treated with anti-mice CD122 antibody was (63.0 ± 12.2)% and (53.2 ± 16.3)%,respectively,which were dramatically higher than that in the mice treated with isotype control antibody (7.7 ± 3.6)% and (6.1 ± 2.4)%. Moreover,at 8 weeks after transplantation,human CD34⁺ cells appeared significantly in the recipients treated with anti-CD122 antibody. It is concluded that the anti-mouse CD122 antibody enhances the hematopoietic repopulating capacity of cord blood CD34⁺ cells in the NOD/SCID mice through decreasing the proportion of NK cells.
Animals ; Antibodies ; immunology ; Antigens, CD34 ; Bone Marrow ; Cord Blood Stem Cell Transplantation ; Fetal Blood ; immunology ; Hematopoietic Stem Cell Transplantation ; Hematopoietic System ; cytology ; immunology ; Humans ; Interleukin-2 Receptor beta Subunit ; immunology ; Killer Cells, Natural ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Transplantation, Heterologous