12,521 research outputs found
Aging and human CD4+ regulatory T cells
No full textAlterations in immunity that occur with aging likely contribute to the development of infection, malignancy and inflammatory diseases. Naturally occurring CD4(+) regulatory T cells (Treg) expressing high levels of CD25 and forkhead box P3 (FOXP3) are essential for regulating immune responses. Here we investigated the effect of aging on the number, phenotypes and function of CD4(+) Treg in humans. The frequency and phenotypic characteristics of CD4(+), FOXP3(+) T cells as well as their capacity to suppress inflammatory cytokine production and proliferation of CD4(+), CD25(-) T cells (target cells) were comparable in young (age <= 40) and elderly (age >= 65) individuals. However, when CD4(+), FOXP3(+) Treg and CD4(+), CD25(-) T cells were co-cultured at a ratio of 1: 1, the production of anti-inflammatory cytokine IL-10 from CD4(+), CD25(-) T cells was more potently suppressed in the elderly than in the young. This finding was not due to changes in CTLA-4 expression orapoptosis of CD4(+), FOXP3(+) Treg and CD4(+), CD25(-) cells. Taken together, our observations suggest that aging may affect the capacity of CD4(+), FOXP3(+) T cells in regulating IL-10 production from target CD4(+) T cells in humans although their other cellular characteristics remain unchanged. (C) 2009 Elsevier Ireland Ltd. All rights reserved.Y
Pyrimidine nucleotide starvation induces a decrease in the number of effector T cells but not memory T cells
No full textY
Dual Roles of IL-15 in Maintaining IL-7RαlowCCR7− Memory CD8+ T Cells in Humans via Recovering the Phosphatidylinositol 3-Kinase/AKT Pathway
No full textRecently, we identified two subsets of CCR7(-) memory CD8(+) T cells expressing high and low levels of the IL-7R alpha-chain (IL-7R alpha) that is essential for memory T cell survival in human peripheral blood. IL-7R alpha(low)CCR7(-) memory CD8(+) T cells that produce effector cytokines and perforin have impaired proliferation and survival in response to TCR triggering and IL-7, respectively. These findings raise a question of how such cells are sustained at significant numbers, > 20% of peripheral CD8(+) T cells, despite impaired IL-7- and TCR-mediated cell maintenance. In this study, we demonstrate that IL-7R alpha(low)CCR7(-) memory CD8(+) T cells have increased expression of IL-2/15R beta-chain (IL-2/15R beta 3), which is critical for IL-15 signaling, with enhanced gene expression of T box expressed in T cells (T-bet) and eomesodermin (eomes), transcriptional factors involved in IL-2/15R beta expression compared with IL-7R alpha(high)CCR7(-) memory CD8(+) T cells. Such a cytokine chain is functional as IL-7R alpha(low)CCR7(-) memory CD8(+) T cells proliferate considerably in response to IL-15. Furthermore, adding IL-15 to TCR'triggering recovers impaired TCR-mediated proliferation of IL-7R alpha(low) memory CD8(+) T cells via restoring the activation of the PI3K/AKT pathway. These findings indicate that IL-15 has dual roles in maintaining IL-7R alpha(low)CCR7(-) memory CD8(+) T cells via TCR-dependent and -independent mechanisms. Moreover, IL-15 can be useful in reviving impaired proliferative function of such memory CD8(+) T cells with effector functions against infections and tumors via rescuing the PI3K/AKT pathway.Y
Effects of host and pathogenicity on mutation rates in avian influenza A viruses
No full textMutation is the primary determinant of genetic diversity in influenza viruses. The rate of mutation, measured in an absolute time-scale, is likely to be dependent on the rate of errors in copying RNA sequences per replication and the number of replications per unit time. Conditions for viral replication are probably different among host taxa, potentially generating the host specificity of the viral mutation rate, and possibly between highly and low pathogenic (HP and LP) viruses. This study investigated whether mutation rates per year in avian influenza A viruses depend on host taxa and pathogenicity. We inferred mutation rates from the rates of synonymous substitutions, which are assumed to be neutral and thus equal to mutation rates, at four segments that code internal viral proteins (PB2, PB1, PA, NP). On the phylogeny of all avian viral sequences for each segment, multiple distinct subtrees (clades) were identified that represent viral subpopulations, which are likely to have evolved within particular host taxa. Using simple regression analysis, we found that mutation rates were significantly higher in viruses infecting chickens than domestic ducks and in those infecting wild shorebirds than wild ducks. Host dependency of the substitution rate was also confirmed by Bayesian phylogenetic analysis. However, we did not find evidence that the mutation rate is higher in HP than in LP viruses. We discuss these results considering viral replication rate as the major determinant of mutation rate per unit time.Y
Down-regulation of IL-7Rα expression in human T cells via DNA methylation
No full textIL-7 is critical for the development and survival of T cells. Recently, we found two subsets of human CD8(+) T cells expressing IL-7R alpha(high) and IL-7R alpha(low) with different cell survival responses to IL-7. Although these CD8(+) T cell subsets have differential IL-7R alpha gene expression, the mechanism for this is unknown. DNA methylation is an important gene regulatory mechanism and is associated with the inactivation of gene expression. Thus, we investigated a role for DNA methylation in differentially regulating IL-7R alpha gene expression in human CD8(+) T cells and Jurkat T cells. IL-7R alpha(high)CD8+ T cells had decreased methylation in the IL-7R alpha gene promoter compared with IL-7R alpha(low)CD8(+) T cells and Jurkat T cells with low levels of IL-7R alpha. Treating Jurkat T cells with 5-aza-2'-deoxycytidine, which reduced DNA methylation, increased IL-7R alpha expression. Plus, the unmethylated IL-7R alpha gene promoter construct had higher levels of promoter activity than the methylated one as measured by a luciferase reporter assay. These findings suggest that DNA methylation is involved in regulating IL-7R alpha expression in T cells via affecting IL-7R alpha gene promoter activity, and that the methylation of this gene promoter could be a potential target for modifying IL-7-mediated T cell development and survival.Y
Tacrolimus regulates endoplasmic reticulum stress-mediated osteoclastogenesis and inflammation: In vitro and collagen-induced arthritis mouse model
No full textTacrolimus is an immunosuppressive drug that inhibits the release of inflammatory cytokines involved in rheumatoid arthritis development by blocking T cell activation. Endoplasmic reticulum stress, an imbalance between protein folding load and capacity leading to the accumulation of unfolded proteins in the endoplasmic reticulum lumen, has been implicated in rheumatoid arthritis and other inflammatory and metabolic diseases. We aimed to investigate the effect of tacrolimus on endoplasmic reticulum stress-mediated osteoclastogenesis and inflammation and elucidate the underlying mechanisms. In vitro studies were performed using mouse bone marrow cells that were cultured with or without interleukin-1, thapsigargin, or tacrolimus to induce osteoclast differentiation. A mouse model of arthritis was established by immunizing mice with bovine type II collagen. Tacrolimus was orally administered to mice from day 20 to 45 following the initial immunization, and histopathological changes and expression of specific biomarkers of endoplasmic reticulum stress-mediated inflammatory signaling pathways were examined. In vitro, tacrolimus inhibited receptor activator of nuclear factor-B ligand-mediated osteoclast formation augmented by interleukin-1, thapsigargin, or both. Furthermore, tacrolimus inhibited glucose-regulated protein (GRP78), protein kinase R-like endoplasmic reticulum kinase, inositol-requiring enzyme 1 (IRE 1), and activating transcription factor 6 (ATF6) augmented by interleukin-1, thapsigargin, or both. Tacrolimus significantly ameliorated osteolysis and endoplasmic reticulum stress intensity in mice. Simultaneously, it reduced inflammatory cell infiltration, osteoclastogenesis, and inflammatory responses by inhibiting GRP78, IRE 1, and ATF6. These findings suggest that tacrolimus exhibits an anti-inflammation effect in rheumatoid arthritis and might inhibit joint damage progression by inhibiting endoplasmic reticulum stress.N
IL-7 and IL-15: Biology and Roles in T-Cell Immunity in Health and Disease
No full textCytokines IL-7 and IL-15 are essentially involved in T-cell homeostasis. IL-7 is required for developing mature T cells in the thymus, whereas in the periphery, it promotes the survival of naive and memory T cells by upregulating the antiapoptotic molecule Bcl-2. IL-15 potently induces the proliferation of memory CD8(+) T cells independently of antigen and augments their effector function. Although IL-7 and IL-15 may help to defend the host against microorganisms and tumors by promoting T-cell immunity, dysregulated production of IL-7 and IL-15 can be harmful. In fact, increased levels of IL-15 in the circulation and inflamed tissues have been reported in various autoimmune diseases, including rheumatoid arthritis (RA), possibly contributing to the pathogenesis. In addition, IL-7, which may induce the production of inflammatory cytokines from T cells and monocytes, are found to be elevated in the joints of patients with RA. Here, we review what is currently known about the roles of these cytokines in T-cell immunity, in general, as well as in RA, in particular, focusing on recent discoveries.N
Autoregulatory function of interleukin-10-producing pre-naïve B cells is defective in systemic lupus erythematosus
No full textIntroduction: Pre-naive B cells represent an intermediate stage in human B-cell development with some functions of mature cells, but their involvement in immune responses is unknown. The aim of this study was to determine the functional role of normal pre-naive B cells during immune responses and possible abnormalities in systemic lupus erythematosus (SLE) that might contribute to disease pathogenesis. Methods: Pre-naive, naive, and memory B cells from healthy individuals and SLE patients were stimulated through CD40 and were analyzed for interleukin-10 (IL-10) production and co-stimulatory molecule expression and their regulation of T-cell activation. Autoreactivity of antibodies produced by pre-naive B cells was tested by measuring immunoglobulin M (IgM) autoantibodies in culture supernatants after differentiation. Results: CD40-stimulated pre-naive B cells produce larger amounts of IL-10 but did not suppress CD4(+) T-cell cytokine production. Activated pre-naive B cells demonstrated IL-10-mediated ineffective promotion of CD4(+) T-cell proliferation and induction of CD4(+)FoxP3(+) T cells and IL-10 independent impairment of co-stimulatory molecule expression and tumor necrosis factor-alpha (TNF-alpha) and IL-6 production. IgM antibodies produced by differentiated pre-naive B cells were reactive to single-stranded deoxyribonucleic acid. SLE pre-naive B cells were defective in producing IL-10, and co-stimulatory molecule expression was enhanced, resulting in promotion of robust CD4(+) T-cell proliferation. Conclusions: There is an inherent and IL-10-mediated mechanism that limits the capacity of normal pre-naive B cells from participating in cellular immune response, but these cells can differentiate into autoantibody-secreting plasma cells. In SLE, defects in IL-10 secretion permit pre-naive B cells to promote CD4(+) T-cell activation and may thereby enhance the development of autoimmunity.Y
Role of Macrophage Migration Inhibitory Factor in the Regulatory T Cell Response of Tumor-Bearing Mice
No full textMacrophage migration inhibitory factor (MIF) is involved in tumorigenesis by facilitating tumor proliferation and evasion of apoptosis; however, its role in tumor immunity is unclear. In this study, we investigated the effect of MIF on the progression of the syngenic, CT26 colon carcinoma and the generation of tumor regulatory T cells (Tregs). The results showed that the tumor growth rate was significantly lower in MIF knockout (MIF-/-) mice than in wild-type (MIF+/+) mice. Flow cytometric analysis of both spleen and tumor cells revealed that MIF-/- mice had significantly lower levels of tumor-associated CD4(+)Tregs than MIF+/+ mice. The splenic cells of MIF-/- mice also showed a decrease in CD8(+)Tregs, which was accompanied by an increase in CD8-induced tumor cytotoxicity. Interestingly, the inducible Treg response in spleen cells to anti-CD3/CD28 plus IL-2 plus TGF-beta was greater in MIF-/- mice than in MIF+/+ mice. Spleen cells of MIF-/- mice, stimulated with anti-CD3/CD28, produced lower levels of IL-2, but not TGF-beta, than those of MIF+/+ mice, which was recovered by the addition of recombinant MIF. Conversely, a neutralizing anti-MIF Ab blocked anti-CD3-induced IL-2 production by splenocytes of MIF+/+ mice and suppressed the inducible Treg generation. Moreover, the administration of IL-2 into tumor-bearing MIF-/- mice restored the generation of Tregs and tumor growth. Taken together, our data suggest that MIF promotes tumor growth by increasing Treg generation through the modulation of IL-2 production. Thus, anti-MIF treatment might be useful in enhancing the adaptive immune response to colon cancers. The Journal of Immunology, 2012, 189: 3905-3913.Y
Proteomic analysis of the biological response of MG63 osteoblast-like cells to titanium implants
No full textUnderstanding of the interaction between human MG63 osteoblast-like cells and surfaces is necessary in the field of tissue engineering and biomaterials. Various titanium surfaces are widely used as not only implant materials, but also as miniscrews in orthodontics. Our goal was to assess the proteomic response of MG63 osteoblast-like cells to different titanium surfaces. MG63 osteoblast-like cells were cultured on three different titanium surfaces: a smooth surface (S), a sandblasted with large grit and acid-etched surface (SLA), and a surface coated with a thin layer of hydroxyapatite (HA). Cells grown on the rougher surfaces (SLA and HA) exhibited downregulated cell proliferation and morphological changes. In the proteomic analysis, cells grown on the SLA surface showed upregulated expression of protocadherin-beta 3 precursor, kinase insert domain receptor, fibroblast growth factor receptor-3, and insulin-like growth factor I, while the expression levels of cell adhesion kinase, collagen alpha-1(I) chain precursor, collagen type XI alpha 2, and cadherin-11 were upregulated in cells grown on the HA surface. These proteins are known to be involved in osteoblast adhesion, growth, and differentiation. Thus, the surface properties of dental materials can influence the expression of proteins involved in osseointegration-related processes. Proteomic analysis may reveal changes in novel proteins that explain why osseointegration varies depending on surface properties.N
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