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Apoptosis Signaling Is Altered in CD4+CD25+FoxP3+ T Regulatory Lymphocytes in Pre-Eclampsia  [PDF]
Dorota Darmochwal-Kolarz,Shigeru Saito,Jacek Tabarkiewicz,Bogdan Kolarz,Jacek Rolinski,Bozena Leszczynska-Gorzelak,Jan Oleszczuk
International Journal of Molecular Sciences , 2012, DOI: 10.3390/ijms13066548
Abstract: The aim of our study was to estimate the surface expressions of CD95 (APO-1/Fas) antigen and the intracellular expressions of anti-apoptotic protein Bcl-2 and pro-apoptotic protein Bax in CD4 +CD25 +FoxP3 + T regulatory lymphocytes (Tregs) as well as the percentage of CD8 +CD28 + T cytotoxic cells in peripheral blood of patients with pre-eclampsia in comparison with healthy pregnant women in the third trimester of physiological pregnancy. Twenty-four women with pre-eclampsia and 20 normal third trimester pregnant women were included in the study. The lymphocytes were isolated from peripheral blood samples and labeled with monoclonal antibodies. The expressions of surface antigens and intracellular proteins were estimated using flow cytometry. The population of CD4 +CD25 +FoxP3 + Treg cells was significantly lower in peripheral blood of patients with pre-eclampsia when compared to normal third trimester pregnant women. The percentages of CD4 +CD25 +FoxP3 + Treg cells that express Bcl-2 protein were significantly lower in peripheral blood of patients with pre-eclampsia when compared to healthy pregnant women, whereas the percentages of CD4 +CD25 +FoxP3 + Treg cells with the expressions of Bax protein did not differ in both groups. Moreover, the mean fluorescence intensity (MFI) of Bcl-2 protein in CD4 +CD25 +FoxP3 + Treg cells was significantly lower and MFI of Bax protein significantly higher in pre-eclampsia when compared to the control group. The percentage of CD8 +CD28 + T cells did not differ in both studied groups but MFI of CD28 antigen on T CD8 + cells was significantly higher in pre-eclampsia when compared to the control group. The obtained results suggest that the deficit of CD4 +CD25 +FoxP3 + Treg lymphocytes which is observed in pre-eclampsia may be associated with altered apoptosis signaling in Tregs.
Efficient induction of CD25- iTreg by co-immunization requires strongly antigenic epitopes for T cells
Shuang Geng, Yang Yu, Youmin Kang, George Pavlakis, Huali Jin, Jinyao Li, Yanxin Hu, Weibin Hu, Shuang Wang, Bin Wang
BMC Immunology , 2011, DOI: 10.1186/1471-2172-12-27
Abstract: In the present study, we demonstrated the requirement of highly antigenic epitopes for CD25- iTreg induction. Firstly, we showed that the induction of CD25- iTreg by tolerogenic DC can be blocked by anti-MHC-II antibody. Next, both the number and the suppressive activity of CD25- iTreg correlated positively with the overt antigenicity of an epitope to activate T cells. Finally, in a mouse model of dermatitis, highly antigenic epitopes derived from a flea allergen not only induced more CD25- iTreg, but also more effectively prevented allergenic reaction to the allergen than did weakly antigenic epitopes.Our data thus indicate that efficient induction of CD25- iTreg requires highly antigenic peptide epitopes. This finding suggests that highly antigenic epitopes should be used for efficient induction of CD25- iTreg for clinical applications such as flea allergic dermatitis.The inducible regulatory T cells, or iTreg, differ from the naturally regulatory T cells (nTreg) in that the former are generated in the periphery through encounter with environmental antigens. It is also believed that iTreg play non-overlapping roles, relative to nTreg, in regulating peripheral tolerance [1-3]. Most iTreg reported to date have been CD25+ cells (CD4+CD25+Foxp3+), and it is well established that their induction requires suboptimal stimulation of the T cell receptor (TCR) and cytokines TGF-β and IL-2 [3]. The CD25+ iTreg thus appear to derive primarily from weakly stimulated CD4+ T cells.We previously identified a different subset of iTreg in mice that is CD25- (CD4+CD25-Foxp3+ and IL-10+TGF-beta+IFN-γ-). The CD25- iTreg were induced after co-immunization using a protein antigen and a DNA vaccine encoding the same antigen [4-7]. Unlike that of the CD25+ iTreg, the induction of the CD25- iTreg involved the generation of CD40low IL-10high tolerogenic dendritic cells (DCs), which in turn stimulated CD25- iTreg in an antigen-specific manner [4]. We further showed in mouse models that this
The role of stromal mast cells in the modification of CD4 CD25 Foxp3 regulatory T cells, Th17 lymphocytes and cytotoxic lymphocytes Tc1 in the development and progression of tumor  [PDF]
Katarzyna Starska,Ewa Brzezińska-B?aszczyk
Post?py Higieny i Medycyny Do?wiadczalnej , 2010,
Abstract: Despite the lack of direct evidence that immune surveillance cells protect against tumor development, indirect clinical observations and experimental studies indicate activity in the immune response against cancer cells of various origin. Little is known about the effects of the stromal tumor mast cell (MC) in the activity of immune cells, i.e. CD4[sup] [/sup]CD25[sup] [/sup]Foxp3[sup] [/sup] regulatory T cells, Th17 lymphocytes, cytotoxic lymphocytes Tc1 and their mutual modulatory function and regulation of the antitumor immune response. Factors synthesized by stromal tumor mast cells including histamine, COX-2, CXCL8 (IL-8), VEGF, IL-6, TNF, iNOS, MMP-8, and MMP-9 may, on the one hand, directly affect the activity of T lymphocyte subpopulations, i.e. iTreg, Tc1, and Th17, and thus regulate immunological processes occurring in the vicinity of the tumor. On the other hand, through effects on angiogenesis, apoptosis, the cell cycle, secretion of cytokines and the expression of adhesion molecules, they may indirectly determine the progression of the neoplasm. Understanding the regulatory mechanisms occurring in the system: tumor stroma mast cell → immune cells infiltrating the tumor (iTreg, Tc1, Th17 lymphocytes) → expression of factors involved in angiogenesis, apoptosis, the cell cycle, and secretion of cytokines and adhesion molecules creates the future possibility of influencing the activation and regulation of selected proneoplastic and antineoplastic factors appearing in the neoplasm environment. Research on these mechanisms may be the beginning of a new approach to the fight against cancer growth and provide an opportunity to introduce new methods of treatment. The aim of this study was to present the current knowledge on the role of stromal tumor CD117[sup] [/sup] mast cells and factors secreted by these cells in the activation of T lymphocyte subpopulations, i.e. CD4[sup] [/sup]CD25[sup] [/sup]Foxp3[sup] [/sup]regulatory T cells, Th17 lymphocytes, and cytotoxic lymphocytes Tc1, as well as to present their impact on the degree of tumor invasiveness by regulating the synthesis of factors secreted by the lymphocyte subpopulations studied, e.g. IL-10 and TGF-β (iTreg), IL-17A and IL-6 (Th17), IFN-γ and IL-2 (Tc1).
Correlation of Local FOXP3-Expressing T Cells and Th1-Th2 Balance in Perennial Allergic Nasal Mucosa  [PDF]
Hideaki Shirasaki,Etsuko Kanaizumi,Nobuhiko Seki,Tetsuo Himi
International Journal of Otolaryngology , 2011, DOI: 10.1155/2011/259867
Abstract: Regulatory T cells (Treg) play some important roles in allergic rhinitis. The most specific marker for Treg is FOXP3, a recently identified transcription factor that is essential for Treg development. In order to clarify the levels of Treg in allergic nasal mucosa, we studied the relationship between FOXP3-expressing cells and Th1-Th2 balance in nasal mucosa by means of immunohistochemistry. Human turbinates were obtained after turbinectomy from 26 patients (14 patients with perennial allergic rhinitis and 12 patients with nonallergic rhinitis). To identify the cells expressing the FOXP3 protein, double immunostaining was performed by using anti-FOXP3 antibody and anti-CD3 antibody. There was no significant difference in the percentage of FOXP3+CD3+ cells among CD3+ cells in the nasal mucosa of two groups. The proportion of FOXP3+CD3+ cells tend to be correlated positively with GATA3+CD3+ cells/T-bet+CD3+ cells ratio ( , ). A positive correlation with GATA3+CD3+/T-bet+CD3+ ratio and FOXP3+CD3+/CD3+ ratio suggests the role of local regulatory T cells as a minimal control of the chronic allergen exposure in nasal mucosa. 1. Introduction The allergic response is a complex process characterized by an aberrant immune response to inhaled environmental allergens. CD4+ lymphocytes with a Th2 phenotype may play some important roles in the development of allergic rhinitis, and the suppression of Th2 lymphocytes could have the potential to be new therapeutic targets for the treatment of allergic rhinitis. The CD4+ CD25+ regulatory T (Treg) cells have been shown to suppress both Th1 and Th2 responses in vitro [1–3]. The most specific marker for Treg cells is FOXP3 as identified transcription factor that is essential for the development of Treg cells. Impaired skin infiltration of CD4+CD25+FOXP3+ T cells was observed in acute atopic dermatitis lesions [4], suggesting a dysregulated control of inflammation by Treg cells. With regard to the local FOXP3-expressing cells in allergic nasal mucosa, conflicting results have been reported regarding difference in the levels of FOXP3-expressing cells in between allergic and nonallergic nasal mucosa. In the present study, we evaluated the number of FOXP3+ cells and the frequencies of FOXP3+ T lymphocytes in perennial allergic and nonallergic nasal mucosa by dual-immunofluorescence methods. 2. Material and Methods 2.1. Subjects Human inferior turbinates were obtained after turbinectomy from 26 patients with nasal obstruction refractory to medical therapy. Informed consent was obtained from all patients and this study was
Fermented fish oil suppresses T helper 1/2 cell response in a mouse model of atopic dermatitis via generation of CD4+CD25+Foxp3+ T cells  [cached]
Han Sang-Chul,Kang Gyeoung-Jin,Ko Yeong-Jong,Kang Hee-Kyoung
BMC Immunology , 2012, DOI: 10.1186/1471-2172-13-44
Abstract: Background Allergic skin inflammation such as atopic dermatitis (AD), which is characterized by pruritus and inflammation, is regulated partly through the activity of regulatory T cells (Tregs). Tregs play key roles in the immune response by preventing or suppressing the differentiation, proliferation and function of various immune cells, including CD4+ T cells. Recent studies report that fermentation has a tremendous capacity to transform chemical structures or create new substances, and the omega-3 polyunsaturated fatty acids (n-3 PUFAs) in fish oil can reduce inflammation in allergic patients. The beneficial effects of natural fish oil (NFO) have been described in many diseases, but the mechanism by which fermented fish oil (FFO) modulates the immune system and the allergic response is poorly understood. In this study, we produced FFO and tested its ability to suppress the allergic inflammatory response and to activate CD4+CD25+Foxp3+ Tregs. Results The ability of FFO and NFO to modulate the immune system was investigated using a mouse model of AD. Administration of FFO or NFO in the drinking water alleviated the allergic inflammation in the skin, and FFO was more effective than NFO. FFO treatment did increase the expression of the immune-suppressive cytokines TGF-β and IL-10. In addition, ingestion of FFO increased Foxp3 expression and the number of CD4+CD25+Foxp3+ Tregs compared with NFO. Conclusions These results suggest that the anti-allergic effect of FFO is associated with enrichment of CD4+CD25+ Foxp3+ T cells at the inflamed sites and that FFO may be effective in treating the allergic symptoms of AD.
Forkhead Transcription Factor FOXP3 Upregulates CD25 Expression through Cooperation with RelA/NF-κB  [PDF]
Cristina Camperio, Silvana Caristi, Giorgia Fanelli, Marzia Soligo, Paola Del Porto, Enza Piccolella
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048303
Abstract: Considerable evidence supports the prediction that CD25 is directly regulated by the forkhead transcription factor FOXP3. However, given that CD25 is normally upregulated in activated T cells, regardless of whether they express FOXP3, this issue has still to be definitively demonstrated. Here we describe that FOXP3, induced by CD28 signals in human CD4+CD25? T lymphocytes, synergizes with RelA on a regulatory region of Cd25 promoter to mediate the transcriptional activation of Cd25 gene. We found that a striking feature of this regulatory region is the presence of a κB site and of two tandem copies of a non-consensus FOXP3 binding site separated at 5′ ends by 19 nucleotides that allow FOXP3 and RelA binding to DNA and their physical interaction. The occupancy of the two FOXP3 binding sites in conjunction with RelA binding site occupancy allows FOXP3 to function as a positive activator of Cd25 gene. Indeed mutations of both FOXP3 binding sites such as mutation of κB site on Cd25 promoter abolished FOXP3 activatory functions. Moreover, FOXP3 mutation ΔE251, that compromises FOXP3 homotypic interactions, failed to trans activate Cd25 promoter, suggesting that both FOXP3 DNA binding and dimerization are required to trans activate Cd25 promoter. These findings identify a novel mechanism by which RelA and FOXP3 cooperate to mediate transcriptional regulation of target genes and characterize a region on Cd25 promoter where FOXP3 dimer could bridge intramolecularly two DNA sites and trans activate Cd25 gene.
Sublingual Immunotherapy Induces Regulatory Function of IL-10-Expressing CD4+CD25+Foxp3+ T Cells of Cervical Lymph Nodes in Murine Allergic Rhinitis Model  [PDF]
Takaya Yamada,Miki Tongu,Kaoru Goda,Noriaki Aoi,Ichiro Morikura,Takafumi Fuchiwaki,Hideyuki Kawauchi
Journal of Allergy , 2012, DOI: 10.1155/2012/490905
Abstract: Sublingual immunotherapy (SLIT) has been considered to be a painless and efficacious therapeutic treatment of allergic rhinitis which is known as type I allergy of nasal mucosa. Nevertheless, its mechanisms need to be further investigated. In this study, we constructed an effective murine model of sublingual immunotherapy in allergic rhinitis, in which mice were sublingually administered with ovalbumin (OVA) followed by intraperitoneal sensitization and nasal challenge of OVA. Sublingually treated mice showed significantly decreased specific IgE responses as well as suppressed Th2 immune responses. Sublingual administration of OVA did not alter the frequency of CD4+CD25+ regulatory T cells (Tregs), but led to upregulation of Foxp3- and IL-10-specific mRNAs in the Tregs of cervical lymph nodes (CLN), which strongly suppressed Th2 cytokine production from CD4+CD25? effector T cells in vitro. Furthermore, sublingual administration of plasmids encoding the lymphoid chemokines CCL19 and CCL21-Ser DNA together with OVA suppressed allergic responses. These results suggest that IL-10-expressing CD4+CD25+Foxp3+ Tregs in CLN are involved in the suppression of allergic responses and that CCL19/CCL21 may contribute to it in mice that received SLIT. 1. Introduction Allergic rhinitis is a Th2-mediated disorder characterized by antigen-specific IgE production and several nasal symptoms such as sneezing, nasal congestion, itching, and rhinorrhea [1]. Crosslinking of the IgE-Fcε receptor complexes by allergen leads to the degranulation of mast cells and basophils, so that histamine and other allergy-associated chemical mediators are released for the immediate phases of allergic responses. Chemokines such as CCL5 (RANTES), CCL11 (eotaxin), CCL17 (thymus and activation-regulated chemokine), and CCL22 (macrophage-derived chemokine) are released by mast cells and other cells and trigger recruitment of inflammatory cells including eosinophils and Th2 cells for the induction of late-phase allergic responses [2, 3]. Allergen-specific immunotherapy has been employed to redirect inappropriate immune responses in patients with allergic rhinitis [4]. Subcutaneous inoculation of allergen has been shown to modulate allergen-specific T cell and B-cell responses and reduce the recruitment and activation of proinflammatory cells in the target mucosa [5]. Subcutaneous immunotherapy (SCIT) significantly reduces symptoms and medication requirements in patients with allergic rhinitis but its use is limited by the possibility of severe systemic reactions [6]; therefore sublingual
Expansion of CD4+CD25+ and CD25- T-Bet, GATA-3, Foxp3 and RORγt Cells in Allergic Inflammation, Local Lung Distribution and Chemokine Gene Expression  [PDF]
You Lu,Carina Malmh?ll,Margareta Sj?strand,Madeleine R?dinger,Serena E. O'Neil,Jan L?tvall,Apostolos Bossios
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019889
Abstract: Allergic asthma is associated with airway eosinophilia, which is regulated by different T-effector cells. T cells express transcription factors T-bet, GATA-3, RORγt and Foxp3, representing Th1, Th2, Th17 and Treg cells respectively. No study has directly determined the relative presence of each of these T cell subsets concomitantly in a model of allergic airway inflammation. In this study we determined the degree of expansion of these T cell subsets, in the lungs of allergen challenged mice. Cell proliferation was determined by incorporation of 5-bromo-2′-deoxyuridine (BrdU) together with 7-aminoactnomycin (7-AAD). The immunohistochemical localisation of T cells in the lung microenvironments was also quantified. Local expression of cytokines, chemokines and receptor genes was measured using real-time RT-PCR array analysis in tissue sections isolated by laser microdissection and pressure catapulting technology. Allergen exposure increased the numbers of T-bet+, GATA-3+, RORγt+ and Foxp3+ cells in CD4+CD25+ and CD4+CD25- T cells, with the greatest expansion of GATA-3+ cells. The majority of CD4+CD25+ T-bet+, GATA-3+, RORγt+ and Foxp3+ cells had incorporated BrdU and underwent proliferation during allergen exposure. Allergen exposure led to the accumulation of T-bet+, GATA-3+ and Foxp3+ cells in peribronchial and alveolar tissue, GATA-3+ and Foxp3+ cells in perivascular tissue, and RORγt+ cells in alveolar tissue. A total of 28 cytokines, chemokines and receptor genes were altered more than 3 fold upon allergen exposure, with expression of half of the genes claimed in all three microenvironments. Our study shows that allergen exposure affects all T effector cells in lung, with a dominant of Th2 cells, but with different local cell distribution, probably due to a distinguished local inflammatory milieu.
The Ratios of CD8+ T Cells to CD4+CD25+ FOXP3+ and FOXP3- T Cells Correlate with Poor Clinical Outcome in Human Serous Ovarian Cancer  [PDF]
Claudia C. Preston, Matthew J. Maurer, Ann L. Oberg, Daniel W. Visscher, Kimberly R. Kalli, Lynn C. Hartmann, Ellen L. Goode, Keith L. Knutson
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0080063
Abstract: Ovarian cancer is an immune reactive malignancy with a complex immune suppressive network that blunts successful immune eradication. This suppressive microenvironment may be mediated by recruitment or induction of CD4+ regulatory T cells (Tregs). Our study sought to investigate the association of tumor-infiltrating CD4+CD25+FOXP3+ Tregs, and other immune factors, with clinical outcome in serous ovarian cancer patients. We performed immunofluorescence and quantification of intraepithelial tumor-infiltrating triple positive Tregs (CD4+CD25+FOXP3+), as well as CD4+CD25+FOXP3-, CD3+ and CD8+ T cells in tumor specimens from 52 patients with high stage serous ovarian carcinoma. Thirty-one of the patients had good survival (i.e. > 60 months) and 21 had poor survival of < 18 months. Total cell counts as well as cell ratios were compared among these two outcome groups. The total numbers of CD4+CD25+FOXP3+ Tregs, CD4+CD25+FOXP3-, CD3+ and CD8+ cells were not significantly different between the groups. However, higher ratios of CD8+/CD4+CD25+FOXP3+ Treg, CD8+/CD4+ and CD8/CD4+CD25+FOXP3- cells were seen in the good outcome group when compared to the patients with poor outcome. These data show for the first time that the ratios of CD8+ to both CD4+CD25+FOXP3+ Tregs and CD4+CD25+FOXP3- T cells are associated with disease outcome in ovarian cancer. The association being apparent in ratios rather than absolute count of T cells suggests that the effector/suppressor ratio may be a more important indicator of outcome than individual cell count. Thus, immunotherapy strategies that modify the ratio of CD4+CD25+FOXP3+ Tregs or CD4+CD25+FOXP3- T cells to CD8+ effector cells may be useful in improving outcomes in ovarian cancer.
CD4+CD25+FOXP3+ Regulatory T Cells In Allogeneic Hematopoietic Cell Transplantation  [cached]
Young-Ho Lee,Muhaimin Rifa'i
Journal of Tropical Life Science , 2011,
Abstract: CD4+CD25+FOXP3+ regulatory T cells (Treg) require activation through the T cell receptor for function. CD4+CD25+FOXP3+ regulatory T cells are believed to be key players of the immune tolerance network and control the induction and effector phase of the immune system. Although these cells require antigen-specific activation, they are generally able to suppress bystander T cell responses once activated. This raises the possibility that antigen-specific Treg may be useful therapeutically by localizing generalized suppressive activity to tissues expressing select target antigens. Treg can exert a potent suppressive effect on immune effector cells reactive to host antigens and prevent graft versus host disease (GVHD) in allogeneic bone marrow transplantation (BMT). Here, we observed that co-transfer of CD4+CD25+FOXP3+ T cells derived from donor type along with the donor bone marrow cells could control GVHD-like reactions by suppressing effectors cells of host responding to the donor hematopoietic compartment, and resulted in prevention of autoimmunity and rejection. We further demonstrate that CD4+CD25+FOXP3+ regulatory T cells can control immune-based morbidity after allogeneic BMT by suppressing the development of granulocytes cells and increasing the level of B cell expression.
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