CD4+CD25+ regulatory T cells down-regulate co-stimulatory molecules on antigen-presenting cells
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CD4+CD25+ T cells have been shown to inhibit experimentally induced organ-specific autoimmune disease and depletion of these regulatory T cells from normal mice results in development of such conditions. Furthermore, CD4+CD25+ T cells suppress the IL-2 production and thereby the proliferation of polyclonally activated CD4+CD25– T cells in vitro. The suppression in vitro is independent of secreted factors but requires interactions between CD4+CD25– and CD4+CD25+ T cells and antigen-presenting cells (APC). We have now further investigated the function of CD4+CD25+ T cells in vitro and have focused on their interactions with APC. We found that CD4+CD25+ T cells down-regulated the expression of the co-stimulatory molecules CD80 and CD86 on dendritic cells. The steady-state level of CD80 mRNA was also decreased, while the steady-state level of CD86 mRNA was not, suggesting that distinct mechanisms regulate the expression of these molecules. The down-regulation occurred even in the presence of stimuli that would normally increase the expression of CD80 and CD86 molecules. Thus, down-regulation of co-stimulatory molecules may be an additional effector function of these regulatory T cells.Keywords:
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Abstract We studied how the interaction between human dendritic cells (DC) and Toxoplasma gondii influences the generation of cell-mediated immunity against the parasite. We demonstrate that viable, but not killed, tachyzoites of T. gondii altered the phenotype of immature DC. DC infected with viable parasites up-regulated the expression of CD40, CD80, CD86, and HLA-DR and down-regulated expression of CD115. These changes are indicative of DC activation induced by T. gondii. Viable and killed tachyzoites had contrasting effects on cytokine production. DC infected with viable T. gondii rather than DC that phagocytosed killed parasites induced secretion of high amounts of IFN-γ by T cells from T. gondii-seronegative donors. IFN-γ production in response to DC infected with viable parasites required CD28 and CD40 ligand (CD40L) signaling. In addition, this IFN-γ response was dependent in part on IL-12 secretion. Production of IL-12 p70 occurred after interaction between T cells and DC infected with viable T. gondii, but not after incubation of T cells with DC plus killed tachyzoites. IL-12 synthesis was inhibited by blockade of CD40L signaling. IL-12-independent IFN-γ production required CD80/CD86-CD28 interaction and, to a lesser extent, CD40-CD40L signaling. Taken together, T. gondii-induced activation of human DC is associated with T cell production of IFN-γ through CD40-CD40L-dependent release of IL-12 and through CD80/CD86-CD28 and CD40-CD40L signaling that mediate IFN-γ secretion even in the absence of bioactive IL-12.
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ABSTRACT C57BL/6 (B6) mice infected with LP-BM5 retroviruses develop disease, including an immunodeficiency similar to AIDS. This disease, murine AIDS (MAIDS), is inhibited by in vivo anti-CD154 monoclonal antibody treatment. The similar levels of insusceptibility of CD40 −/− and CD154 −/− B6 mice indicate that CD154/CD40 molecular interactions are required for MAIDS. CD4 + T and B cells, respectively, provide the CD154 and CD40 expression needed for MAIDS induction. Here, the required CD154/CD40 interaction is shown to be independent of CD80 and CD86 expression: CD80/CD86 −/− B6 mice develop MAIDS after LP-BM5 infection.
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Objective:To investigate the effect of transplant tolerance induced by CD40-CD40L costimulation blockade on the function of DCs.Methods:The mouse recipients with heterotopic heart transplantation were administrated with anti-CD40L mAb(MR-1) to induced the transplant tolerance.DCs were sorted from rejected and tolerant recipients using MACS.Their expression of CD40,CD80 and CD86 was examined using FACS.DCs were stimulated with LPS in vitro and IL-10,IL-12 levels in the supernatants were evaluated using ELISA.We also investigated their stimulatory capability and tolerogenic capability using mixed leukocyte reaction(MLR).Results:DCs from tolerant recipients expressed lower CD40,CD80,CD86,and secreted higher level of IL-10 and lower level of IL-12.Furthermore,DCs from tolerant recipients were weak stimulators of the MLR and inhibited the proliferation of splenocytes.Conclusion:IL-10highIL-12low DCs with immature phenotype were induced in the transplant tolerance with treatment of CD40-CD40L costimulation blockade and they obtained the tolerogenic function.
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Background Atherosclerosis is a disease triggered by diverse exogenous stimuli and sustained by chronic inflammatory processes. Dendritic cells (DCs) are key regulatory antigen-presenting cells and play a crucial role in regulating the adaptive and innate immune system in any chronic inflammatory process. DCs are present in atherosclerotic lesions in the areas of the highest T-cell density. So far, their role in atherosclerosis has not been fully elucidated. We investigated the phenotypic properties of DCs in patients with coronary artery disease (CAD) in comparison to healthy individuals. Methods Peripheral blood monocytes were isolated from 50 patients with CAD and 19 healthy individuals and differentiated over 9 days to immature and mature DCs. Analysis of the distribution of important stimulatory and costimulatory molecules on the surface of immature and mature DCs was performed by flow cytometry. Results We observed no changes between the groups concerning cell numbers or expression of CD1a or HLA-DR on DCs. Patients with CAD, however, showed a significant upregulation of the costimulatory molecules CD80, CD86 and CD40 as compared with healthy controls. Expression of CD40, CD80 and CD86 on DCs partly correlated with smoking, family history of CAD, as well as with C-reactive protein levels. High-density lipoprotein cholesterol was inversely associated with the expression of CD40 and CD80 on mature DCs (P<0.05). Conclusion Upregulation of important costimulatory molecules on monocyte-derived DCs of CAD patients, is influenced multifactorially. Our results show notable differences between CAD patients and healthy individuals, possibly contributing to the pathophysiological processes in atherogenesis.
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Objective Dendritic cells(DC) play an important role in the initiation of immunologic response.This study aims to investigate the changes in the subgroups and surface markers of DCs derived from the peripheral blood of the aged people. MethodsMononuclear cells were isolated from the peripheral blood of 30 aged people(≥80 yr) and 30 elderly controls(60-70 yr) and cultured with hGM-CSF and hIL-4 for a week to obtain DCs.The percentages of the subgroups of DCs(DC1 and DC2) in the leukocytes were detected by flow cytometry.Changes in the DC surface markers CD1a,HLA-DR,CD80(B7-1),CD86(B7-2),CD40,CCR-7 and CD209 of the aged people were observed and compared with those of the elderly controls.Results Both the percentage of DC1 in the peripheral blood leukocytes and the DC1/DC2 ratio were lower in the aged group than in the elderly controls,and so were the rate of the CD1a positive cells and the expressions of the DC CD40,CD80,CD86 and CD209 molecules.Conclusion The subgroups of DCs and their surface markers undergo changes with aging,which may be involved in the pathogenesis of immune senescence.
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Background. The response of human CD4+ T cells against porcine cells is of comparable magnitude to that induced by human leukocyte antigen-mismatched allogeneic cells. This reflects productive interactions between key costimulatory molecules across the species barrier. Inhibition of these molecular interactions will be crucial in overcoming CD4+ T-cell–mediated rejection of xenografts. We have performed a detailed investigation to determine the expression profiles and relative contributions of the three key costimulatory molecules in the porcine-human xenogeneic response. Whereas only porcine CD86 is constitutively expressed on resting endothelial cells, both CD40 and CD80 are rapidly expressed after activation. All three costimulatory molecules are expressed by professional antigen-presenting cells. Methods. We have isolated full-length cDNA clones for human and porcine CD80, CD86, and CD40. Human fibroblast cell lines (M1) coexpressing DR1 were transfected with these cDNAs and used in mixed lymphocyte reactions and flow cytometric studies in vitro. Results. These data provide the first characterization of the expression profile and functional role of porcine CD80. Functional assays demonstrate that pCD40, pCD80, and pCD86 are independently capable of costimulating human CD4+ T cells, albeit with differing kinetics. Proliferative responses were of comparable magnitude to those obtained when costimulation was provided by human CD40, CD80, and CD86. Conclusions. These data have implications for therapy targeting the direct pathway of xenorecognition; costimulatory molecule blockade must be directed against both the B7/CD28 and CD40/CD40L pathways.
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T cells express CD28 and CD27 which transduce co-stimulatory signals after interaction with their ligands on antigen-presenting cells (APC). These ligands, CD80, CD86 and CD70, are also expressed to some extent on activated T cells. Here, we show that in human immunodeficiency virus (HIV)-infected individuals, CD28 and CD27 expression is decreased on CD8+ T cells. On the other hand, T cell stimulation in vitro induced high CD80, CD86 and CD70 expression on T cells from HIV-infected individuals. It appeared that an inverted CD4:CD8 T cell ratio could explain this enhanced expression of co-stimulatory ligands. Indeed, high expression levels of CD80, CD86 and CD70 were found on activated CD8+ T cells from HIV- individuals cultured in the absence of CD4+ T cells. Addition of CD4+ T cells prevented this up-regulation. However, in HIV-infected individuals, addition of excess autologous or healthy control CD4+ T cells did not completely counteract up-regulation of co-stimulatory ligand expression on CD8+ T cells. Thus, to some extent, CD8+ T cells in HIV-infected individuals appeared to be refractory to CD4+ T cell-mediated regulation of ligand expression in vitro. Activated T cells from HIV-infected individuals and activated CD8+ T cells from healthy controls were able to act as accessory cells in CD3-induced T cell proliferation, which was dependent on cell-cell contact. Thus, we showed that T cells from HIV-infected individuals express enhanced levels of co-stimulatory ligands upon activation, which provides them with accessory cell properties. Enhanced stimulatory potential of these nonprofessional APC may contribute to persistently high levels of immune activation in HIV infection related to disease progression.
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Objective To compare the phenotypes of bone marrow derived dendritic cell(BMDC)and DC2.4 cell stimulated with GST from Schistosoma japonicum.Methods Bone marrow cells were cultured in the presence of IL-4 and GM-CSF to induce dendritic cells.DC2.4 cells were cultured as routine.Both cells were stimulated with GST and the expressions of CD40,CD80 and CD86 on the cells'surface were analyzed by FACS,using PBS and lipopolysaccharide as controls. Results After stimulating with GST,the means of fluorescence intensity(MFI)for CD40,CD80 and CD86 on BMDC surface were 100.39,42.38 and 170.83,respectively.Compared with PBS control,the MFI of CD80 and CD86 on BMDC,but not CD40,enhanced significantly.The MFIs of CD40.CD80 and CD86 on DC2.4 loaded by GST were 23.73,72.13 and 59.58 respectively.Compared with PBS control,the expressions of CD40 and CD86 enhanced significantly after schistosome antigen stimulation.Conclusion The expressions of cell surface molecules after schistosome antigen GST stimulation were different between BMDC and DC2.4.
Key words:
Schistosoma japonicum; Dendritic cell; DC2.4; Phenotype
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