Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.79 (granzyme B)
3,301 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infiltration of CD3(+)CD8(+) cytotoxic T cells was analyzed by multiparameter confocal laser microscopy in a panel of 16 randomly selected stage I nonsmall cell lung carcinomas. T-cell infiltration was observed in the stroma (range 57-2,093 T cells/mm(2)) but also in the tumor epithelium (range 21-892 T cells/mm(2)) and showed wide variation between individual tumors. Interestingly, a significantly higher percentage of CD3(+)CD8(+) T cells was detected in the tumor epithelium compared to the stroma illustrating that cytotoxic T cells may preferentially migrate into tumor epithelium. Aberrant HLA class I antigen expression was observed in 69% of the nonsmall-cell lung carcinoma (NSCLC) tumors. One tumor of a squamous cell lung carcinoma patient with the highest number of tumor infiltrating CD3(+) and CD3(+)CD8(+) cells was studied in detail and the majority (90%) of these cells were shown to be functionally activated granzyme B-positive cytotoxic T cells. DNA oligotyping of a lung carcinoma cell line established from this tumor revealed loss of one HLA haplotype corresponding with a translocation involving chromosome 6, as observed by COBRA-FISH. HLA class I-restricted tumor specific T cells could be isolated from PBMC. One further characterized cytotoxic CD8(+) T cell clone, that released TNF-alpha, IFN-gamma, and granzyme B upon co-incubation with the autologous tumor cells, was shown to be restricted by the remaining HLA-A11 allele, which was also shown to be expressed in the tumor tissue. Our data indicate that, despite HLA-haplotype loss a vigorous antitumor immune response mediated by CD8(+ )T-cells can be present in NSCLC offering possibilities for specific immunotherapy.
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PMID:Functional CD8+ T cells infiltrate into nonsmall cell lung carcinoma. 1692 94

Although CD4+CD25+FoxP3+ regulatory T cells play a role in allograft tolerance, the role of CD8+ cells with immunosuppressive function is less clear. To address this issue, spleen cells from Rag-1-deficient TCR transgenic (Tg) mice expressing a receptor for ovalbumin (OVA) in the context of MHC class I (OT1) were activated with OVA expressing antigen-presenting cell (APC) in the presence or absence of exogenous transforming growth factor beta (TGFbeta). TGFbeta inhibited the expression of IFN-gamma, granzyme B and the lytic activity of the OT1 T cells while inducing FoxP3 expression in 5-15% of the cells. By contrast, FoxP3 expression was not detected in naive OT-1 T cells or OT-1 T cells activated without exogenous TGFbeta. TGFbeta-activated OT1 cells inhibited the activation of Kd-specific CD8+ CTL responses by normal B6 T cells and the proliferation by Kd-specific CD4+ TCR Tg T cells, but only if the OVA epitope was co-expressed by Kd+ APC. This antigen-specific inhibitory activity, referred to as linked suppression, was neither mediated by residual lytic activity within the activated OT1 T cells nor did it depend upon IL-10 or TGFbeta. Suppression correlated with inhibition of CD86 expression on CD11c+ APC. TGFbeta-activated OT1 T cells also delayed the rejection of heterotopic, vascularized cardiac allografts mediated by anti-Kd-specific CD4+ TCR Tg T cells, but only if the cardiac allograft expressed both OVA and Kd as transgenes. Prolonged survival of allografts was associated with rapid migration of the FoxP3+ OT1 T cells into the donor heart raising the possibility that suppression may be mediated within the allograft. These data show that TGFbeta-activated CD8+ T cells mediate antigen-specific, APC-focused patterns of suppression in vitro and in vivo.
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PMID:TCR transgenic CD8+ T cells activated in the presence of TGFbeta express FoxP3 and mediate linked suppression of primary immune responses and cardiac allograft rejection. 1696 95

The Bcr-Abl tyrosine kinase inhibitor imatinib mesylate is highly effective in the front-line treatment of chronic myeloid leukemia (CML) and is increasingly used in patients with residual disease or relapse after allogeneic stem cell transplantation (allo-SCT). Since an impairment of anti-viral CD8+ T-lymphocyte function by imatinib has been described, we question whether imatinib also affects specific anti-leukemic CD8+ T lymphocytes generated from the peripheral blood of healthy donors, and of CML patients after allo-SCT. Here, we assessed CD8+ T-cell expansion and function from healthy donors and patients with CML. The release of IFN-gamma and granzyme B by CD8+ T-lymphocytes specific for R3, a recently described T-cell epitope peptide derived from a leukemia-associated antigen designated RHAMM/CD168 (receptor for hyaluronic acid mediated motility), was inhibited by imatinib in a dose-dependent fashion (range: 1-25 microM). These T cells were able to lyse cognate peptide labeled T2 cells and CD34+ CML progenitor cells. This lysis was inhibited by imatinib. The inhibitory effect was not associated with an increased rate of apoptosis of T cells and reversible after removal of imatinib. In the light of these findings, clinical administration of imatinib might result in the reduction of efficacy of the graft-versus-leukemia effect or other T-cell-based immunotherapies.
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PMID:Imatinib impairs CD8+ T lymphocytes specifically directed against the leukemia-associated antigen RHAMM/CD168 in vitro. 1700 43

Human T cell lymphotropic virus type 1 (HTLV-1)-specific CTL are thought to be immune effectors that reduce the risk of adult T cell leukemia (ATL). However, in vivo conditions of anti-HTLV-1 CTL before and after ATL development have yet to be determined. To characterize anti-HTLV-1 CTL in asymptomatic HTLV-1 carriers (AC) and ATL patients, we analyzed the frequency and diversity of HTLV-1-specific CD8+ T cells in PBMC of 35 AC and 32 ATL patients using 16 distinct epitopes of HTLV-1 Tax or Env/HLA tetramers along with intracellular cytolytic effector molecules (IFN-gamma, perforin, and granzyme B). Overall frequency of subjects possessing Tax-specific CD8+ T cells was significantly lower in ATL than AC (53 vs 90%; p = 0.001), whereas the difference in Env-specific CD8+ T cells was not statistically significant. AC possessed Tax11-19/HLA-A*0201-specific tetramer+ cells by 90% and Tax301-309/HLA-A*2402-specific tetramer+ cells by 92%. Some AC recognized more than one epitope. In contrast, ATL recognized only Tax11-19 with HLA-A*0201 and Tax301-309 with HLA-A*2402 at frequencies of 30 and 55%. There were also significant differences in percentage of cells binding Tax11-19/HLA-A*0201 and Tax301-309/HLA-A*2402 tetramers between AC and ATL. Anti-HTLV-1 Tax CD8+ T cells in AC and ATL produced IFN-gamma in response to Tax. In contrast, perforin and granzyme B expression in anti-HTLV-1 CD8+ T cells of ATL was significant lower than that of AC. Frequency of Tax-specific CD8+ T cells in AC was related to proviral load in HLA-A*0201. These results suggest that decreased frequency, diversity, and function of anti-HTLV-1 Tax CD8+ T cell clones may be one of the risks of ATL development.
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PMID:Reduced frequency, diversity, and function of human T cell leukemia virus type 1-specific CD8+ T cell in adult T cell leukemia patients. 1701 61

Dendritic cells (DC) resident in draining lymph nodes (LN) of patients with lung cancer are proposed to have a critical role in stimulating anti-tumor immunity. CpG oligodeoxynucleotides are undergoing clinical trials in patients with lung cancer and are likely to target plasmacytoid-DC. The present study, therefore, investigated the capacity of plasmacytoid-DC from human lung cancer draining LN to respond to CpG for activation of T cell responses relevant to anti-tumor immunity. The phenotype of DC was examined by flow cytometry, and cytokine production by cytometric bead array (CBA) and ELISA. Plasmacytoid-DC, purified by cell sorting, were immature but expressed the toll-like receptor, TLR9. Plasmacytoid-DC responded to the CpG oligodeoxynucleotide, CpG 2216, by production of the proinflammatory cytokines, IFN-alpha and IL-6. DC were cocultured with normal, allogeneic T cells, and cytokine production determined by CBA and immunophenotyping. CpG 2216 enhanced IFN-gamma production and induced intracellular production of IFN-gamma by CD8(+) and CD4(+), granzyme B by CD8(+), and IL-2 by CD4(+) T cells, respectively. Ligation of CD40 on plasmacytoid-DC combined with exposure to CpG 2216 also strongly enhanced IFN-gamma production. There was no significant difference between the responses of plasmacytoid-DC from patients with lung cancer and patients with benign carcinoid tumors with no pathologic LN involvement. These results indicate that plasmacytoid DC from the draining LN of patients with lung cancer effectively induce Tc1 immunity and could, therefore, represent a novel and attractive target for immunotherapeutic intervention.
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PMID:Plasmacytoid dendritic cells from human lung cancer draining lymph nodes induce Tc1 responses. 1702 87

Immunization of cattle with a Leptospira borgpetersenii serovar hardjo-bovis vaccine results in the development of a recall response by WC1(+) gammadelta T cells and CD4(+) alphabeta T cells characterized by proliferation and interferon-gamma production. It was hypothesized that these two T cell subpopulations had largely redundant effector functions, principally differing in their requirements for activation. To test this, gene expression in cells proliferating to antigen were compared utilizing RT-PCR and bovine microarrays. Both T cell populations had similar transcript profiles for effector molecules, including IFN-gamma, FasL and granzyme B. In contrast, transcripts for costimulatory receptors and ligands were notably different following activation, as WC1(+) T cells expressed no or lower levels of transcripts for CD28 and CD40L, while CD4(+) T cells expressed substantial levels of both. However, both cell types had high levels of CTLA-4 transcript suggesting the cells may be regulated similarly following activation but differ in their need for and ability to provide costimulation. Microarray analyses to extend the number of genes examined revealed that while both subpopulations upregulated anti-apoptotic genes as well as those involved in cell activation and protein biosynthesis, overall there were limited differences between the two antigen-activated cell populations. Those genes that did differ were involved in cell signaling, protein production and intracellular protein trafficking. These results strengthen the hypothesis that these particular activated WC1(+) and CD4(+) T cells have overlapping effector functions and therefore may differ principally with regard to how they are recruited into immune responses.
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PMID:Comparison of gene expression by co-cultured WC1+ gammadelta and CD4+ alphabeta T cells exhibiting a recall response to bacterial antigen. 1708 9

A single intratumoral injection of IL-12 and GM-CSF-loaded slow-release microspheres induces T cell-dependent eradication of established primary and metastatic tumors in a murine lung tumor model. To determine how the delivery of cytokines directly to the microenvironment of a tumor nodule induces local and systemic antitumor T cell activity, we characterized therapy-induced phenotypic and functional changes in tumor-infiltrating T cell populations. Analysis of pretherapy tumors demonstrated that advanced primary tumors were infiltrated by CD4+ and CD8+ T cells with an effector/memory phenotype and CD4+CD25+Foxp3+ T suppressor cells. Tumor-associated effector memory CD8+ T cells displayed impaired cytotoxic function, whereas CD4+CD25+Foxp3+ cells effectively inhibited T cell proliferation demonstrating functional integrity. IL-12/GM-CSF treatment promoted a rapid up-regulation of CD43 and CD69 on CD8+ effector/memory T cells, augmented their ability to produce IFN-gamma, and restored granzyme B expression. Importantly, treatment also induced a concomitant and progressive loss of T suppressors from the tumor. Further analysis established that activation of pre-existing effector memory T cells was short-lived and that both the effector/memory and the suppressor T cells became apoptotic within 4 days of treatment. Apoptotic death of pre-existing effector/memory and suppressor T cells was followed by infiltration of the tumor with activated, nonapoptotic CD8+ effector T lymphocytes on day 7 posttherapy. Both CD8+ T cell activation and T suppressor cell purge were mediated primarily by IL-12 and required IFN-gamma. This study provides important insight into how local IL-12 therapy alters the immunosuppressive tumor milieu to one that is immunologically active, ultimately resulting in tumor regression.
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PMID:Reversing tumor immune suppression with intratumoral IL-12: activation of tumor-associated T effector/memory cells, induction of T suppressor apoptosis, and infiltration of CD8+ T effectors. 1708 11

NK cells are key components of innate immune systems and their activities are regulated by cytokines and hormones. All-trans retinoic acid (ATRA), as a metabolite of vitamin A and an immunomodulatory hormone, plays an important role in regulating immune responses. In the present study, we investigated the effect of ATRA on human NK cell line NK92. We found that ATRA dose-dependently suppressed cytotoxic activities of NK92 cells without affecting their proliferation. To explore the mechanisms underlying the ATRA influence on NK92 cells, we examined the production of cytokines (TNF-alpha, IFN-gamma), gene expression of cytotoxic-associated molecules (perforin, granzyme B, nature killer receptors (NCRs), and NKG2D), and the activation of NF-kappaB pathways related with immune response. Our results demonstrated that ATRA suppressed NF-kappaB activity and prevented IkappaBalpha degradation in a dose-dependent way, inhibited IFN-gamma production and gene expression of granzyme B and NKp46. Our findings suggest that ATRA is a negative regulator of NK92 cell activation and may act as a potential regulator of anti-inflammatory functions in vivo.
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PMID:All-trans retinoic acid negatively regulates cytotoxic activities of nature killer cell line 92. 1710 66

Constitutive presentation of tissue Ags by dendritic cells results in tolerance of autoreactive CD8+ T cells; however, the underlying molecular mechanisms are not well understood. In this study we show that programmed death (PD)-1, an inhibitory receptor of the CD28 family, is required for tolerance induction of autoreactive CD8+ T cells. An antagonistic Ab against PD-1 provoked destructive autoimmune diabetes in RIP-mOVA mice expressing chicken OVA in the pancreatic islet cells, which received naive OVA-specific CD8+ OT-I cells. This effect was mediated by the PD ligand (PD-L) PD-L1 but not by PD-L2. An increased number of effector OT-I cells recovered from the pancreatic lymph nodes of anti-PD-L1-treated mice showed down-regulation of PD-1. Furthermore, the blockade of PD-1/PD-L1 interaction during the priming phase did not significantly affect OT-I cell division but enhanced its granzyme B, IFN-gamma, and IL-2 production. Thus, during the presentation of tissue Ags to CD8+ T cells, PD-1/PD-L1 interaction crucially controls the effector differentiation of autoreactive T cells to maintain self-tolerance.
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PMID:Cutting Edge: Programmed death (PD) ligand-1/PD-1 interaction is required for CD8+ T cell tolerance to tissue antigens. 1714 23

Since CCR6 is a receptor for the chemokine CCL20, which is produced in tissues such as intestine and colon, it is thought that T cells expressing CCR6 are involved in mucosal immunity. The expression and function of CCR6 on human CD8+ T cells have not well been analyzed, although it is known that this receptor is expressed on a subset of human CD8+ T cells. We here characterize human CCR6+ CD8+ T cells. Multi-color flow cytometric analysis demonstrated that CCR6+ cells are predominantly found among CD8+ T cells having the memory phenotype. The expression of CCR6 is positively and negatively correlated with that of CCR5 and CCR7, respectively. CCR6+ CD8+ T cells express granzyme A and a low level of perforin but not granzyme B. In addition, a major population among these cells has the ability to produce IFN-gamma and TNF-alpha but not IL-2. These results indicate that CCR6+ CD8+ T cells have characteristics of early effector memory cells rather than effector or central memory cells. A chemotaxis assay revealed that CCR6+ CD8+ T cells have the ability to migrate in response to CCL20, suggesting that these T cells migrate to tissues such as colon and are involved in mucosal immunity.
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PMID:Functional expression of chemokine receptor CCR6 on human effector memory CD8+ T cells. 1717 55


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