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At least 19 recordsLinked to original sources
PubMed2004

Steroid therapy altered serum levels of CCL2 and CCL5 chemokines in multiple sclerosis patients during relapse.

Chemokines are involved in the pathogenesis of multiple sclerosis. The aim of this study was to determine the impact of steroid therapy on the levels of CCL2 and CCL5 chemokines. The study encompassed 30 patients with clinically definite relapsing-remitting multiple sclerosis who were treated with methylprednisolone due to the relapse of the disease. The control groups consisted of 20 patients during the stable stage of relapsing-remitting multiple sclerosis and of 15 patients with noninflammatory diseases of the nervous system. Both chemokines were markedly expresssed in serum by enzyme-linked immunosorbent assay. During relapse, the levels of both chemokines differed significantly from the levels measured in both control groups. After the methylprednisolone treatment, the chemokine levels changed significantly: the levels of CCL2 increased, whilst the levels of CCL5 decreased. These alterations did not correlate with the clinical state of the patients or with the therapeutic effect of the treatment and indicated that the inflammatory reaction accompanying the relapse was receding.

Adult↗
PubMedDate not supplied

[Concentration of the beta-chemokine CCL5 (RANTES) in cerebrospinal fluid in patients with tick-borne encephalitis].

BACKGROUND AND PURPOSE: In tick-borne encephalitis (TBE), perivascular infiltrates are formed within the central nervous system (CNS) and are accompanied by pleocytosis with a predominance of T CD4+ lymphocytes in cerebrospinal fluid (CSF). Factors responsible for leukocyte flow into CNS in TBE have not been investigated. We evaluated the concentration of the chemotactic factor for lymphocytes, chemokine CCL5 (RANTES, Regulated upon Activation, Normal T cell Expressed and Secreted) in CSF and serum of patients with TBE and assessed its correlation with CSF pleocytosis. MATERIAL AND METHODS: Group I consisted of 10 patients with TBE virus infection presenting as meningitis; group II included 11 patients with TBE presenting as encephalomeningitis or myeloencephalomeningitis. The control group consisted of 8 patients, in whom neuroinfection and infection with TBE virus was excluded. The concentration of CCL5 was measured by ELISA in CSF and serum samples taken within 24 hours after hospitalization (examination 1) and in the convalescence period, on average after 16 days (examination 2). RESULTS: Mean CCL5 concentration in serum did not differ between the groups, while in CSF it was significantly increased in group I (64.3+/-75.5 pg/ml in examination 1 and 44.4+/-39.5 pg/ml in examination 2) and in group II (38.4+/-17.0 pg/ml in examination 1 and 48.8+/-24.7 pg/ml in examination 2) in comparison with controls (3.7+/-5.3 pg/ml). There was no significant difference regarding CCL5 concentration between groups I and II and between the examination 1 and 2. There was no correlation between the concentration of CCL5 and CSF parameters. CONCLUSIONS: The concentration of CCL5 is increased in CSF, but not in serum of patients with TBE. This increase does not depend on the clinical form of the disease and is sustained after the disappearance of the symptoms of acute infection. Further studies are necessary to determine the source of CCL5, and its role in the pathogenesis of TBE and its sequelae.

Adult↗
PubMed2006

The chemokine CCL5 as a potential prognostic factor predicting disease progression in stage II breast cancer patients.

PURPOSE: The aim of this study was to determine the prognostic value of the chemokine CCL5, considered as a promalignancy factor in breast cancer, in predicting breast cancer progression and to evaluate its ability to strengthen the prognostic significance of other biomarkers. EXPERIMENTAL DESIGN: The expression of CCL5, alone and in conjunction with estrogen receptor (ER)-alpha, ER-beta, progesterone receptor (PR), and HER-2/neu (ErbB2), was determined in breast tumor cells by immunohistochemistry. The study included 142 breast cancer patients, including individuals in whom disease has progressed. RESULTS: Using Cox proportional hazard models, univariate analysis suggested that, in stage I breast cancer patients, CCL5 was not a significant predictor of disease progression. In contrast, in stage II patients, the expression of CCL5 (CCL5(+)), the absence of ER-alpha (ER-alpha(-)), and the lack of PR expression (PR(-)) increased significantly the risk for disease progression (P = 0.0045, 0.0041, and 0.0107, respectively). The prognostic strength of CCL5, as well as of ER-alpha(-), improved by combining them together (CCL5(+)/ER-alpha(-): P = 0.0001), being highly evident in the stage IIA subgroup [CCL5(+)/ER-alpha(-) (P = 0.0003); ER-alpha(-) (P = 0.0315)]. In the stage II group as a whole, the combinations of CCL5(-)/ER-alpha(+) and CCL5(-)/PR(+) were highly correlated with an improved prognosis. Multivariate analysis indicated that, in stage II patients, ER-alpha and CCL5 were independent predictors of disease progression. CONCLUSIONS: CCL5 could be considered as a biomarker for disease progression in stage II breast cancer patients, with the CCL5(+)/ER-alpha(-) combination providing improved prediction of disease progression, primarily in the stage IIA subgroup.

Adult↗
PubMed2006

Expression of the inflammatory chemokines CCL5, CCL3 and CXCL10 in juvenile idiopathic arthritis, and demonstration of CCL5 production by an atypical subset of CD8+ T cells.

This study focuses upon three chemokines, namely CCL5, CXCL10 and CCL3, which are potential novel therapeutic targets in arthritis. The aim of the study was to analyse the expression and production of these three chemokines within the joints of children with juvenile idiopathic arthritis (JIA) of the oligoarticular and polyarticular subtypes. All three of these chemokines are highly expressed at the level of mRNA, with the most significant increase in mRNA levels being demonstrated for CCL5 when compared with matched peripheral blood samples and controls. We show that high levels of all three chemokines are present in synovial fluid of children with JIA. We investigate the major source of CCL5 from inflammatory synovial cells, which we show to be CD8+ T cells. This CD8+ synovial T cell population has an unexpected phenotype that has not been described previously, being CCR7- yet predominantly CD28+ and CD45RA-. These cells contain high levels of stored intracellular CCL5, and rapid release of CCL5 takes place on T cell stimulation, without requiring new protein synthesis. In addition, we demonstrate that CCL5 is present in synovial biopsies from these patients, in particular on the endothelium of small and medium sized vessels. We believe this to be the first in depth analysis of these mediators of inflammation in JIA.

Adult↗
PubMed2003

The chemokines CCL5, CCL2 and CXCL12 play significant roles in the migration of Th1 cells into rheumatoid synovial tissue.

As the T-cell population in the synovial tissue (ST) in rheumatoid arthritis (RA) is dominated by T helper (Th) 1 cells, this study was designed to examine whether there is a preferential migration of polarized T cells to ST, and to identify the chemokines responsible for the migration. This was done by developing 10 T-cell clones specific for an arbitrary antigen (mouse immunoglobulin G (IgG)) from the peripheral blood (PB) of a healthy donor sensitized to mouse IgG. The Th polarizations of the clones were determined by measuring secreted interferon-gamma and interleukin-4, following anti-CD3 stimulation. Migration to pools of RA ST cell-derived supernatants was analysed. Expression of the chemokine receptors CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CXCR3 and CXCR4 were analysed by flow cytometry. Th1 clones showed significantly higher migration to RA ST cell-derived supernatant compared with Th2 clones. Blocking of either of the chemokines, CCL5 or CCL2, strongly inhibited migration of the Th1 cells between 56 and 77%, while blocking of CXCL12 inhibited migration between 44 and 61%. Blocking of CXCL10 had only a minor inhibitory effect. Our results demonstrate a selective migration of Th1 cells to RA ST supernatant and that blocking either CCL5, CCL2 or CXCL12 significantly inhibits T-cell migration. This indicates that CCL5, CCL2 and CXCL12 play significant roles in attracting Th1 cells towards the RA ST, and may prove potent targets for obstructing T-cell migration to the synovium.

Arthritis, Rheumatoid↗
PubMed2005

Renal transplantation: examination of the regulation of chemokine binding during acute rejection.

BACKGROUND: Chemokines recruit leukocytes during allograft rejection. It is thought that the formation of glycosaminoglycan (GAG)-stabilized chemokine concentration gradients within the allograft plays a crucial role in this process. This raises the possibility that changes in GAG biology might regulate chemokine binding and the development of rejection. METHODS: Immunocytochemical techniques were used to quantify changes in GAG expression within normal and rejection renal biopsy sections. Changes in GAG expression by cultured endothelial cell lines were also examined after stimulation with tumor necrosis factor-alpha and interferon-gamma. Quantitative reverse-transcriptase polymerase chain reaction was used to examine the basis for increased sulphation of heparan sulphate (HS) observed during inflammation. A binding assay was developed to determine how levels of GAG expression correlate with changes in chemokine (CCL5) sequestration. RESULTS: In normal kidney, HS was largely restricted to the tubular basement membrane; chondroitin-4-sulphate and chondroitin-6-sulphate were expressed within the interstitial tissues. The expression of all three GAGs was increased significantly during acute rejection, and heavily sulphated HS remained predominant within the tubular basement membrane. Treatment of endothelial cells with proinflammatory cytokines increased the expression of mRNA encoding N-deacetylase/N-sulphotransferase-1, an isoform of the enzyme responsible for N-sulphation of HS. Cytokine-treated cells and rejection biopsy specimens showed an enhanced capacity to bind CCL5. CONCLUSIONS: Chemokine production is known to be increased during acute renal allograft rejection. In this study we showed that the graft tissues also respond by increasing their potential to bind chemokines, a process that is vital for effective chemokine presentation and leukocyte recruitment.

Amidohydrolases↗
PubMed2005

Generation of GPI-linked CCL5 based chemokine receptor antagonists for the suppression of acute vascular damage during allograft transplantation.

Limiting the acute vascular damage associated with leukocyte infiltration is a central issue in solid organ transplantation. The family of chemotactic cytokines (chemokines) helps to regulate leukocyte recruitment. Systemic treatment with the chemokine ligand-5 (CCL5) based antagonist Met-RANTES has previously shown to suppress acute damage to transplanted kidneys by blocking effector cell recruitment. To address problems associated with systemic long-term administration of chemokine receptor antagonists, a chemokine based reagent was designed to be integrated into endothelial surfaces of the organ just before transplantation. Proteins anchored by glycosylphosphatidylinositol (GPI), when purified and added to cells, are efficiently incorporated into their cell surface membranes. A series of modifications were introduced into the CCL5 protein to generate a functional antagonist. These included the addition of an N-terminal methionine group, a mutation to render the protein a dimer and a GPI signal sequence for surface expression. The resultant protein was stably expressed in CHO cells, GPI anchorage was confirmed and the protein purified by FPLC. Exogenously administered Met-CCL5(dimer)-GPI was efficiently inserted into the membrane of microvascular endothelial cells. The reagent is being tested in murine models of renal transplantation. The effect on subsequent immune induced damage will be assessed.

Acute Disease↗
PubMed2005

Emergence of immune escape variant of mammary tumors that has distinct proteomic profile and a reduced ability to induce "danger signals".

Breast tumors are shaped, in part, by a process termed immunoediting which selects for immunologically evasive phenotypes. In the present study we used the rat neu-transgenic mouse model of breast cancer and its congenic non-transgenic parental strain, FVB, to explore the phenotype of tumors that emerge in the presence of an immune response directed against the neu antigen. When inoculated into parental FVB mice, a neu-overexpressing mouse mammary carcinoma (MMC) cell line isolated from spontaneous breast tumors of the FVB neu (FVBN202) transgenic mouse, elicited a neu-specific immune response resulting in a tumor rejection because of the presence of the rat neu antigen. However, a neu negative variant (ANV) of MMC arose after a long latency in spite of the neu-specific immune response. We show that compared to MMC, ANV tumor cells have a significantly reduced ability to secrete pro-inflammatory cytokines and the CCL5 chemokine, to express immunostimulatory chaperones, and they have a distinct expression of proteins involved in cell motility, and metabolic and signal transduction pathways. These studies suggest that tumor escape through immunoediting can not be explained by the loss of a single tumor antigen, but rather by a selection process of a tumor variant that has a reduced ability to induce "danger signals" together with up-regulation of proteins involved in the tumor survival. Based on these findings, we propose to target novel antigens over-expressed in the escape variant of breast tumors to treat primary tumor and to prevent tumor relapse.

Animals↗
PubMed2003

A dual role for tumor-derived chemokine RANTES (CCL5).

To investigate the role of tumor-derived CCL5 (regulated upon activation, normal T cell expressed and secreted, RANTES) in tumor immunity we compared the T cell response to tumors derived from the 4T1 murine mammary carcinoma cell line that express different levels of CCL5. Tumors that expressed low levels of CCL5 exhibited a decrease in the in vivo, but not the in vitro, growth rate. In conjunction with the decreased growth rate the tumors that produced lower levels of CCL5 contained a greater number of tumor infiltrating lymphocytes compared to tumors that express normal levels of CCL5. One explanation for these findings was that a reduction in tumor-derived CCL5 prevented the tumor-associated alteration in T cell chemotactic activity. Tumors expressing lower levels of CCL5 also elicited a greater tumor-specific T cell response as evident by examination of recently activated T cells from tumor-draining lymph nodes. However, despite the enhanced T cell response, tumors expressing low levels of CCL5 still grew slower than tumors expressing normal levels of CCL5 in SCID mice. These data are consistent with the ability of CCL5 to upregulate transcription of matrix metalloproteinase-9 (MMP9), which can contribute to angiogenesis and thus, foster growth in vivo. Consequently, these data indicate that tumor-derived CCL5 can inhibit the T cell response and enhance the in vivo growth of murine mammary carcinoma.

Animals↗
PubMed2002

Dendritic cells exposed to extracellular adenosine triphosphate acquire the migratory properties of mature cells and show a reduced capacity to attract type 1 T lymphocytes.

We previously reported that chronic stimulation with low, noncytotoxic doses of extracellular adenosine triphosphate (ATP) induced a distorted maturation of dendritic cells (DCs) and impaired their capacity to initiate T-helper (Th) 1 responses in vitro. Here, we examined the effects of ATP on chemokine-receptor expression and chemokine production by DCs. ATP strongly induced expression of CXC chemokine receptor 4 on both immature and lipopolysaccharide (LPS)-stimulated DCs and slightly up-regulated CC chemokine receptor (CCR) 7 on both DC types. In contrast, ATP reduced CCR5 expression on immature DCs. These effects were confirmed at both the messenger RNA and protein levels and were not produced by uridine triphosphate (UTP). Consistent with the changed receptor expression, ATP increased migration and intracellular calcium of immature and mature DCs to stromal-derived factor 1 (CXC ligand [CXCL] 12) and macrophage inflammatory protein [MIP] 3 beta (CC ligand [CCL] 19), whereas responses to MIP-1 beta (CCL4) were reduced. DCs are an important source of chemokines influencing recruitment of distinct T-lymphocyte subsets. ATP, but not UTP, significantly reduced LPS-induced production of interferon-inducible protein 10 (CXCL10) and regulated upon activation, normal T-cell expressed and secreted chemokine (CCL5); increased secretion of macrophage-derived chemokine (CCL22); and did not change production of thymus and activation-regulated chemokine (CCL17). Consistent with these findings, supernatants from ATP-treated mature DCs attracted Th1 and T-cytotoxic 1 cells less efficiently, whereas migration of Th2 and T cytotoxic 2 cells was not affected. Our data suggest that ATP provides a signal for enhanced lymph node localization of DCs but that it may, at the same time, diminish the capacity of DCs to amplify type 1 immune responses.

Adenosine Triphosphate↗
PubMed2004

Inhibition of respiratory syncytial virus infection with the CC chemokine RANTES (CCL5).

Respiratory syncytial virus (RSV) is a major cause of respiratory tract disease in infants, aged adults, and immunosuppressed patients. The only approved medicines for RSV disease are administration of prophylatic antibodies or treatment with a synthetic nucleoside. Both approaches are expensive and the latter is not without risk and of controversial benefit. The present investigation studied whether pharmaceutical or biologic compounds based upon chemokines might be useful in preventing RSV disease. Of interest was RANTES/CCL5, which inhibits infection by HIV strains that use chemokine receptor (CCR)-5 as co-receptor. Herein, we report that prior or simultaneous treatment of HEp-2 cells with recombinant human CCL5 provides dose-dependent inhibition of infection with RSV. Other recombinant chemokines (MIP-1alpha/CCL3, MIP-1beta/CCL4, MCP-2/CCL8, eotaxin/CCL11, MIP-1delta/CCL15, stromal cell derived factor (SDF)-1alpha/CXCL12) were not inhibitory. The data suggested that CCL5 might inhibit infection by blocking fusion (F) protein-epithelial cell interactions. Infections by mutant RSV strains deleted of small hydrophobic and/or attachment proteins and only expressing F protein in the envelope were inhibited by prior treatment with CCL5 or a biologically inactive N-terminally modified met-CCL5. Inhibition was also observed when virus adsorption and treatment with CCL5 were performed at 4 degrees C. Flow cytometry further revealed that epithelial cells were positive for CCR3, but not CCR1 or CCR5. Thus, novel mimetics of CCL5 may be useful prophylatic agents to prevent respiratory tract disease caused by RSV.

Antiviral Agents↗
PubMed2005

Tissue trafficking patterns of effector memory CD4+ T cells in rheumatoid arthritis.

OBJECTIVE: Clonal populations of CD4+,CD28- T cells accumulating in rheumatoid arthritis functionally resemble end-differentiated, nondividing, short-lived effector memory cells that reside in peripheral tissues. We undertook this study to examine the tissue niche for CD4+,CD28- T cells and the signals regulating their survival and tissue homing patterns. METHODS: Chemokine receptor expression on CD4+,CD28- T cell clones and peripheral blood lymphocytes was assessed by multicolor cytometry. In vitro chemotaxis and transendothelial migration were examined in a Transwell system. In vivo tissue-homing patterns were established by adoptively transferring fluorescence-labeled T cell clones into SCID mice engrafted either with rheumatoid synovium or with human lymph nodes. RESULTS: CD4+,CD28- T cell clones adoptively transferred into human tissue-SCID mouse chimeras infiltrated rheumatoid synovium but preferentially homed to lymph nodes. Such T cells coexpressed the chemokine receptors CCR7, CCR5, and CXCR4 and migrated in response to both inflammatory chemokines (CCL5) and homing chemokines (CXCL12). T cell receptor crosslinking abrogated chemotactic responsiveness. In contrast, interleukin-12 stimulation induced the up-regulation of CCR5 and a shift in the in vivo homing pattern away from the lymph nodes toward the inflamed synovium. CONCLUSION: CD4+,CD28- T cells resemble both short-lived effector memory cells and long-lived central memory cells, and they find a niche both in inflamed synovium and in lymph nodes. Nonspecific cytokine stimulation, not antigen recognition, triggers the transition from the lymph node to the synovium. By maintaining CCR7 expression, these end-differentiated T cells can home to lymphoid organs, enhance their survival, support clonal expansion, and perpetuate autoreactivity.

Adoptive Transfer↗
PubMed2006

Shear flow-dependent integration of apical and subendothelial chemokines in T-cell transmigration: implications for locomotion and the multistep paradigm.

Lymphocyte extravasation requires that emigrating cells process chemoattractant signals, typically mediated by chemokines, encountered on endothelial surface (apical) and subendothelial (basal) compartments. These signals are delivered under conditions of hemodynamic shear, a fundamental feature of all physiologic leukocyte-endothelial interactions. To analyze lymphocyte responsiveness to spatially distributed chemokines and their effects on transendothelial migration (TEM) under hydrodynamic shear, we constructed a transwell-based flow assay. We observed that the inflammatory chemokine CCL5 (RANTES) induces negligible human T-cell migration across inflamed human umbilical vascular endothelial cells (HUVECs) when displayed alone in the subendothelial compartment under static or hemodynamic shear conditions or when combined with apical CXCL12 (SDF-1alpha) under static conditions. However, under shear stress, T cells encountering apically presented CXCL12 were primed to undergo robust LFA-1-dependent TEM toward subendothelial CCL5. Notably, locomotive T cells arriving at endothelial junctions were retained and extended pseudopodia into and through the junctions, thereby increasing sensitivity to subendothelial CCL5. These findings provide the first evidence that lymphocytes integrate, conditional to shear forces, permissive apical chemokine deposits, and integrin engagement signals, resulting in morphologic changes and amplified chemotaxis to an otherwise weak subendothelial chemokine signal.

Cells, Cultured↗
PubMed2006

Expression of CCL5 (RANTES) and CCR5 in prostate cancer.

BACKGROUND: Expression of the inflammatory chemokine CCL5 (RANTES) by tumor cells is thought to correlate with the progression of several cancers. CCL5 was shown to induce breast cancer cell migration, mediated by the receptor CCR5. A CCR5 antagonist was demonstrated to inhibit experimental breast tumor growth. Recently, CCL5 and CCR5 mRNA expression was reported in prostate cancer (PCa) tissues. Herein, we characterized CCL5 and CCR5 expression in cultures of PCa cells and explored possible functions of CCL5 in PCa progression. METHODS: Quantitative RT-PCR, ELISA, and immunohistochemical staining were performed to examine CCL5 expression in prostate cell lines. CCR5 expression was measured by flow cytometry. Proliferation and invasion assays were performed to determine potential functions of CCL5 and CCR5 in PCa. RESULTS: Expression of CCL5 mRNA and protein was found in human PCa cell lines (PC-3; DU-145; LNCaP) and primary prostate adenocarcinoma cells. CCL5 and CCR5 were also detected in human PCa tissues. CCR5 expression was demonstrated on the cell surface of PCa cells, as well as in intracellular pools. Incubation with CCL5 (10-100 ng/ml) induced PCa cell proliferation, and the CCR5 antagonist TAK-779 inhibited CCL5-induced proliferation. CCL5 was found to stimulate PCa cell invasion, and TAK-779 blocked the effects of CCL5. CONCLUSIONS: In light of evidence that inflammation influences the pathogenesis of PCa, these results suggest that inflammatory chemokines, such as CCL5, expressed by prostate cells may act directly on the growth and survival of PCa cells. Chemokine receptor antagonists may thus block autocrine mechanisms of PCa progression.

Adenocarcinoma↗
PubMed2005

Chemokine response to febrile urinary tract infection.

BACKGROUND: Mucosal CXC chemokines recruit inflammatory cells to the infected urinary tract. The chemokine response repertoire of the urinary tract and the relationship to disease severity have not been examined, however. METHODS: This study quantified CXC (CXCL1, CXCL3, CXCL5, CXCL8, CXCL9, and CXCL10) and CC (CCL2, CCL4, and CCL5) chemokines in sequential urine samples obtained from 50 patients with febrile urinary tract infections during 24 hours after diagnosis. RESULTS: All patients had elevated chemokine levels, but bacteremic infections caused higher CXCL1, CXCL3, CXCL5, CXCL8, and CCL2 responses. CCL2 and CXCL8 levels were higher in patients with acute pyelonephritis symptoms and CCL2, CXCL3, CCL4, CXCL5, and CXCL10 were significantly correlated to C-reactive protein (CRP) and temperature. Women and men showed different chemokine responses. CONCLUSION: Febrile urinary tract infections are accompanied by a complex chemokine response. The response magnitude reflects disease severity, and the repertoire is influenced by gender and underlying disease.

Adolescent↗
PubMed2006

The strength of the chemotactic response to a CCR5 binding chemokine is determined by the level of cell surface CCR5 density.

We have shown that the intensity of expression of the C-C chemokine receptor CCR5 at the single CD4(+) cell level strongly determines the efficiency of its function as a coreceptor for human immunodeficiency virus type 1. By analogy, we examined if the number of CCR5 molecules at the cell surface might determine its chemotactic response to CCR5 ligands. To test this hypothesis, we measured by flow cytometry the migration of primary human T cells towards the CCR5-binding chemokine CCL5 in vitro. First, we observed a dose-dependent blockage of this migration exerted by an anti-CCR5 monoclonal antibody. Second, we sorted peripheral blood mononuclear cells into five subpopulations expressing various cell surface CCR5 densities, and observed a correlation between the intensity of migration towards CCL5 and the level of CCR5 expression on these subpopulations. Third, we transduced CCR5(+) peripheral blood mononuclear cells with the CCR5 gene, and observed that the CCR5 over-expression induced an over-migration towards CCL5. Finally, we observed in healthy donors a correlation between the chemotactic response of peripheral blood CD8(+) T cell to CCL5 and their level of surface CCR5 expression. T-cell surface CCR5 density, which is constant over time for a given individual, but varies drastically among individuals, might therefore be an important personal determinant of T-cell migration in many biological situations where CCR5-binding chemokines play a role, such as graft rejection, T helper 1-mediated auto-immune diseases, and infectious diseases involving CCR5. Moreover, our data highlight the therapeutic potential of CCR5 antagonists in these situations.

Antibodies, Monoclonal↗
PubMed2005

Coordinate expression of CC chemokine ligand 5, granulysin, and perforin in CD8+ T cells provides a host defense mechanism against Mycobacterium tuberculosis.

The ability of CD8+ T cells to kill intracellular pathogens depends upon their capacity to attract infected cells as well as their secretion of cytolytic and antimicrobial effector molecules. We examined the Ag-induced expression of three immune effector molecules contained within cytoplasmic granules of human CD8+ T cells: the chemokine CCL5, the cytolytic molecule perforin, and the antimicrobial protein granulysin. Macrophages infected with virulent Mycobacterium tuberculosis triggered the expression of CCL5 in CD8+ T cells only in donors with previous exposure to the tuberculosis bacteria, not in naive donors. Functionally, CCL5 efficiently attracted M. tuberculosis-infected macrophages, but failed to exert direct antibacterial activity. Infected macrophages also triggered the expression of granulysin in CD8+ T cells, and granulysin was found to be highly active against drug-susceptible and drug-resistant M. tuberculosis clinical isolates. The vast majority of CCL5-positive cells coexpressed granulysin and perforin. Taken together, this report provides evidence that a subset of CD8+ T cells coordinately expresses CCL5, perforin and granulysin, thereby providing a host mechanism to attract M. tuberculosis-infected macrophages and kill the intracellular pathogen.

Animals↗