scholarly journals Lipoteichoic Acid Inhibits Interleukin-2 (IL-2) Function by Direct Binding to IL-2

2001 ◽  
Vol 8 (5) ◽  
pp. 972-979 ◽  
Author(s):  
Lisa M. Plitnick ◽  
Robert A. Jordan ◽  
Jeffrey A. Banas ◽  
Dawn M. Jelley-Gibbs ◽  
Mary C. Walsh ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
Flow Cytometric Analysis ◽  
Lipoteichoic Acid ◽  
Enzyme Linked Immunosorbent Assay ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Direct Binding

ABSTRACT Lipoteichoic acid (LTA) is associated with the cell envelope of most gram-positive bacteria. Although previously thought to act mainly as a virulence factor by virtue of its adhesive nature, evidence is now provided that LTA can also suppress the function of interleukin-2 (IL-2), an autocrine growth factor for T cells. LTA from four separate bacterial strains lowered the levels of detectable IL-2 during a peripheral blood mononuclear cell response to the antigen tetanus toxoid (TT). T-cell proliferation in response to TT was similarly inhibited by LTA. In contrast, levels of detectable gamma interferon increased. In addition, LTA inhibited IL-2 detection by enzyme-linked immunosorbent assay (ELISA) and blocked the proliferative response of an IL-2-dependent T-cell line to soluble IL-2. Further studies using ELISA demonstrated that LTA blocks IL-2 detection and function by binding directly to IL-2. Flow cytometric analysis revealed that IL-2 binding to T cells is inhibited in the presence of purified LTA but not LTA plus anti-LTA monoclonal antibody. In summary, these studies demonstrate a novel effect of LTA on the immune response through direct binding to IL-2 and inhibition of IL-2 function. Importantly, gram-positive organisms from which LTA is obtained not only play an important role in the pathology of diseases such as bacterial endocarditis, septic shock, acute respiratory distress syndrome, and multiple organ failure but also comprise a significant portion of commensal populations within the human host. Inhibition of IL-2 function by LTA may represent yet another mechanism by which gram-positive bacteria dampen the host immune response and facilitate survival. Thus, LTA provides a potential target for therapeutic intervention when gram-positive organisms are involved.

scholarly journals Human Articular Chondrocytes Induce Interleukin-2 Nonresponsiveness to Allogeneic Lymphocytes

Cartilage ◽  
2016 ◽  
Vol 8 (3) ◽  
pp. 300-306 ◽  
Author(s):  
Satomi Abe ◽  
Hitoshi Nochi ◽  
Hiroshi Ito
Keyword(s):  
T Cells ◽  
Articular Chondrocytes ◽  
Interleukin 2 ◽  
Flow Cytometric Analysis ◽  
Third Party ◽  
Soluble Form ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Activated T Cells ◽  
Allogeneic Lymphocytes

Introduction We previously showed that articular chondrocytes (ACs) have immune privilege and immunomodulatory functions like those of mesenchymal stem cells. To elucidate these mechanisms, we focused on interleukin-2 (IL-2), which plays critical roles in lymphocyte mitogenic activity. The purpose of this study was to explore whether ACs affect the role of IL-2 underlying immunomodulatory functions. Material and Methods Irradiated human ACs from osteoarthritis donors were used. Third-party ACs were added to the mixed lymphocyte reaction (MLR) with or without recombinant human IL-2 (rhIL-2), and the levels of IL-2 and the soluble form of the IL-2 receptor α (sIL-2Rα) protein in supernatant were measured by enzyme-linked immunosorbent assay. Recombinant human IL-2 (rhIL-2) was also added to the MLR. To detect the expression of IL-2 receptor α (CD25) on lymphocytes in the MLR, flow cytometric analysis was performed. Last, ACs and allogeneic activated CD4+ T cell were co-cultured, and the expression of CD25 on activated T cells was examined by flow cytometry. Results Third-party ACs significantly inhibited the MLR and reduced the level of sIL-2Rα in a dose-dependent manner, but did not affect the concentration of IL-2. Exogenous rhIL-2 accelerated MLR but did not rescue the inhibitory effect of ACs. ACs inhibited the expression of CD25 on activated CD4+ T cells. Discussion Our results showed that third-party ACs inhibited the proliferation of allogeneic activated lymphocytes, thereby inhibiting production sIL-2Rα, although ACs did not affect IL-2 secretion from lymphocytes. Also, ACs inhibited CD25 expression on activated CD4+ T cells. Thus, ACs inhibited the immune response of allogeneic lymphocytes by inducing IL-2 nonresponsiveness.

scholarly journals Polarization of Allogeneic T-Cell Responses by Influenza Virus-Infected Dendritic Cells

2000 ◽  
Vol 74 (17) ◽  
pp. 7738-7744 ◽  
Author(s):  
Sangkon Oh ◽  
Maryna C. Eichelberger
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Interleukin 2 ◽  
Dependent Manner ◽  
Ifn Γ ◽  
High Doses ◽  
Type Response

ABSTRACT The developing immune response in the lymph nodes of mice infected with influenza virus has both Th1- and Th2-type characteristics. Modulation of the interactions between antigen-presenting cells and T cells is one mechanism that may alter the quality of the immune response. We have previously shown that the ability of dendritic cells (DC) to stimulate the proliferation of alloreactive T cells is changed by influenza virus due to viral neuraminidase (NA) activity. Here we show that DC infected with influenza virus A/PR/8/34 (PR8) stimulate T cells to produce different types of cytokines in a dose-dependent manner. Optimal amounts of the Th1-type cytokines interleukin-2 (IL-2) and gamma interferon (IFN-γ) were produced from T cells stimulated by DC infected with low doses of PR8, while the Th2-type cytokines IL-4 and IL-10 were produced only in response to DC infected with high doses of PR8. IL-2 and IFN-γ levels corresponded with T-cell proliferation and were dependent on the activity of viral NA on the DC surface. In contrast, IL-4 secretion required the treatment of T cells with NA. Since viral particles were released only from DC that are infected with high doses of PR8, our results suggest that viral NA on newly formed virus particles desialylates T-cell surface molecules to facilitate a Th2-type response. These results suggest that the activity of NA may contribute to the mixed Th-type response observed during influenza virus infection.

An emerging player in the adaptive immune response: microRNA-146a is a modulator of IL-2 expression and activation-induced cell death in T lymphocytes

Blood ◽  
2010 ◽  
Vol 115 (2) ◽  
pp. 265-273 ◽  
Author(s):  
Graziella Curtale ◽  
Franca Citarella ◽  
Claudia Carissimi ◽  
Marina Goldoni ◽  
Nicoletta Carucci ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Activation Induced Cell Death

Abstract Activation of the T cell–mediated immune response has been associated with changes in the expression of specific microRNAs (miRNAs). However, the role of miRNAs in the development of an effective immune response is just beginning to be explored. This study focuses on the functional role of miR-146a in T lymphocyte–mediated immune response and provides interesting clues on the transcriptional regulation of miR-146a during T-cell activation. We show that miR-146a is low in human naive T cells and is abundantly expressed in human memory T cells; consistently, miR-146a is induced in human primary T lymphocytes upon T-cell receptor (TCR) stimulation. Moreover, we identified NF-kB and c-ETS binding sites as required for the induction of miR-146a transcription upon TCR engagement. Our results demonstrate that several signaling pathways, other than inflammation, are influenced by miR-146a. In particular, we provide experimental evidence that miR-146a modulates activation-induced cell death (AICD), acting as an antiapoptotic factor, and that Fas-associated death domain (FADD) is a target of miR-146a. Furthermore, miR-146a enforced expression impairs both activator protein 1 (AP-1) activity and interleukin-2 (IL-2) production induced by TCR engagement, thus suggesting a role of this miRNA in the modulation of adaptive immunity.

scholarly journals Street RABV Induces the Cholinergic Anti-inflammatory Pathway in Human Monocyte-Derived Macrophages by Binding to nAChr α7

2021 ◽  
Vol 12 ◽  
Author(s):  
Carmen W. E. Embregts ◽  
Lineke Begeman ◽  
Cees J. Voesenek ◽  
Byron E. E. Martina ◽  
Marion P. G. Koopmans ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Macrophage Polarization ◽  
Flow Cytometric Analysis ◽  
Human Monocyte ◽  
Host Immune System ◽  
Inflammatory Pathway ◽  
Anti Inflammatory ◽  
Alpha Bungarotoxin

Rabies virus (RABV) is able to reach the central nervous system (CNS) without triggering a strong immune response, using multiple mechanisms to evade and suppress the host immune system. After infection via a bite or scratch from a rabid animal, RABV comes into contact with macrophages, which are the first antigen-presenting cells (APCs) that are recruited to the area and play an essential role in the onset of a specific immune response. It is poorly understood how RABV affects macrophages, and if the interaction contributes to the observed immune suppression. This study was undertaken to characterize the interactions between RABV and human monocyte-derived macrophages (MDMs). We showed that street RABV does not replicate in human MDMs. Using a recombinant trimeric RABV glycoprotein (rRABV-tG) we showed binding to the nicotinic acetylcholine receptor alpha 7 (nAChr α7) on MDMs, and confirmed the specificity using the nAChr α7 antagonist alpha-bungarotoxin (α-BTX). We found that this binding induced the cholinergic anti-inflammatory pathway (CAP), characterized by a significant decrease in tumor necrosis factor α (TNF-α) upon LPS challenge. Using confocal microscopy we found that induction of the CAP is associated with significant cytoplasmic retention of nuclear factor κB (NF-κB). Co-cultures of human MDMs exposed to street RABV and autologous T cells further revealed that the observed suppression of MDMs might affect their function as T cell activators as well, as we found a significant decrease in proliferation of CD8+ T cells and an increased production of the anti-inflammatory cytokine IL-10. Lastly, using flow cytometric analysis we observed a significant increase in expression of the M2-c surface marker CD163, hinting that street RABV might be able to affect macrophage polarization. Taken together, these results show that street RABV is capable of inducing an anti-inflammatory state in human macrophages, possibly affecting T cell functioning.

scholarly journals Flow cytometric analysis of the Hermes homing-associated antigen on human lymphocyte subsets

Blood ◽  
1989 ◽  
Vol 74 (2) ◽  
pp. 751-760 ◽  
Author(s):  
J de los Toyos ◽  
S Jalkanen ◽  
EC Butcher
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Human Lymphocyte ◽  
High Surface ◽  
Interleukin 2 ◽  
Flow Cytometric Analysis ◽  
Surface Glycoprotein ◽  
Lymphoid Tissues ◽  
High Endothelial Venules

Abstract The homing of lymphocytes is controlled by interactions with high endothelial venules (HEV), specialized vessels that define sites of lymphocyte extravasation into lymph nodes and inflamed tissues. In humans, lymphocyte-HEV binding involves a lymphocyte surface glycoprotein (GP) of 85 to 95 kd (CD44, H-CAM), defined by monoclonal antibody (MoAb) Hermes-1. To define the expression of this homing- associated adhesion molecule during human lymphocyte development, we performed two-color immunofluorescence analyses of human bone marrow (BM), thymus, peripheral blood (PB), and tonsillar lymphocytes. The highest levels of Hermes-1 antigen are displayed by circulating B and T cells in the blood, which are uniformly positive and bear roughly twice the level of antigen present on mature lymphocytes within organized lymphoid tissues and BM. “Immature” (CD4+, CD8+) T cells in the thymus are Hermes-1lo to-, whereas thymocytes of mature phenotype (CD4+ or CD8+) are positive. The Hermes-1 antigen is present at high levels on the same population of thymocytes that bears high surface levels of CD3, a component of the T-cell antigen receptor complex, suggesting that levels of T-cell homing and antigen receptors characteristic of mature peripheral T cells appear coordinately during thymocyte maturation/selection. Essentially all T cells in the periphery are Hermes-1hi, including T blasts, and the homing-associated antigen is maintained at high levels on T cells stimulated in vitro by phytohemagglutinin (PHA) and on interleukin-2 (IL-2) maintained T-cell clones and lines. In contrast, although most resting IgD+ B cells are positive a significant fraction of B cells in tonsils are Hermes-1lo to- ; these cells are predominantly PNAhi, IgD-, and CD20hi, a phenotype characteristic of sessile, activated B cells in germinal centers. In all lymphocyte populations examined, there is a linear correlation in staining for Hermes-1 and for Hermes-3, an antibody that defines a distinct functionally important epitope on this molecule. The results demonstrate a precise regulation of this homing-associated antigen during lymphocyte differentiation.

scholarly journals Protective Killed Leptospira borgpetersenii Vaccine Induces Potent Th1 Immunity Comprising Responses by CD4 and γδ T Lymphocytes

2001 ◽  
Vol 69 (12) ◽  
pp. 7550-7558 ◽  
Author(s):  
Brian M. Naiman ◽  
David Alt ◽  
Carole A. Bolin ◽  
Richard Zuerner ◽  
Cynthia L. Baldwin
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Mononuclear Cells ◽  
Flow Cytometric Analysis ◽  
Γδ T Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Specific Response ◽  
Zoonotic Infections ◽  
Leptospira Borgpetersenii ◽  
Ifn Γ

ABSTRACT Leptospira borgpetersenii serovar hardjo is the most common cause of bovine leptospirosis and also causes zoonotic infections of humans. A protective killed vaccine against serovar hardjo was shown to induce strong antigen-specific proliferative responses by peripheral blood mononuclear cells (PBMC) from vaccinated cattle by 2 months after the first dose of vaccine. This response was absent from nonvaccinated control cattle. The mean response peaked by 2 months after completion of the two-dose vaccination regimen, and substantial proliferation was measured in in vitro cultures throughout the 7 months of the study period. Variations in magnitude of the response occurred among the vaccinated animals, but by 7 months postvaccination there was a substantial antigen-specific response with PBMC from all vaccinated animals. Up to one-third of the PBMC from vaccinated animals produced gamma interferon (IFN-γ) after 7 days in culture with antigen, as ascertained by flow cytometric analysis, and significant levels of IFN-γ were measured in culture supernatants by enzyme-linked immunosorbent assay. Two-color immunofluorescence revealed that one-third of the IFN-γ-producing cells were γδ T cells, with the remaining cells being CD4+ T cells. The significance of this study is the very potent Th1-type immune response induced and sustained following vaccination with a killed bacterial vaccine adjuvanted with aluminum hydroxide and the involvement of γδ T cells in the response. Moreover, induction of this Th1-type cellular immune response is associated with the protection afforded by the bovine leptospiral vaccine against L. borgpeterseniiserovar hardjo.

scholarly journals Characteristics of Circulating CD4+ T Cell Subsets in Patients with Mycobacterium avium Complex Pulmonary Disease

2020 ◽  
Vol 9 (5) ◽  
pp. 1331
Author(s):  
Sun Ae Han ◽  
Yousang Ko ◽  
Sung Jae Shin ◽  
Byung Woo Jhun
Keyword(s):  
T Cells ◽  
T Cell ◽  
Pulmonary Disease ◽  
Mycobacterium Avium ◽  
Cd4 T Cells ◽  
Mycobacterium Avium Complex ◽  
Mononuclear Cells ◽  
Flow Cytometric Analysis ◽  
T Cell Subsets ◽  
Enzyme Linked Immunosorbent Assay

Although prevalence of Mycobacterium avium complex pulmonary disease (MAC-PD) is increasing, limited data are available regarding vulnerability to Mycobacterium avium complex (MAC) infections. To understand the pathobiology of interaction between MAC and host-immunity, it is important to understand the characteristics for circulating T cells in terms of the immunological phenotype and functional correlates in MAC-PD. We aimed to characterize immunophenotype, cytokine profile, and immune inhibitory receptors of circulating CD4+ T cells in MAC-PD patients. We enrolled 71 MAC-PD and 20 control individuals. Flow cytometric analysis was performed to determine T cell subsets and immune checkpoint markers. Ex vivo cytokine productions in response to MAC were determined using enzyme-linked immunosorbent assay. The frequencies of CD4+ T cells and CD4+IL-17+ T cells decreased, while CD4+IL-4+ T cells and CD4+CD25+Foxp3+ T cells increased in peripheral blood mononuclear cells (PBMCs) of MAC-PD individuals upon MAC stimulation compared with those cells in healthy donor-PBMCs. Additionally, we found increased PD-1, CTLA-4, and TIM-3-expressing T cells in MAC- PD individuals in response to MAC-stimulation, indicating that suppressed T cell-mediated response is associated with the susceptibility to MAC infection. These results may help to explain impaired T cell-mediated responses and pave the way for better strategies to achieve protective immunity against MAC infection.

scholarly journals Simultaneous flow cytometric analysis of human T cell activation antigen expression and DNA content.

1983 ◽  
Vol 157 (2) ◽  
pp. 461-472 ◽  
Author(s):  
T Cotner ◽  
J M Williams ◽  
L Christenson ◽  
H M Shapiro ◽  
T B Strom ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Flow Cytometric Analysis ◽  
Early Activation ◽  
Activation Antigens ◽  
Activation Antigen

Cell-surface antigens that are induced to appear on T cells activated by the lectin phytohemagglutinin-P (PHA) can be classified both on the basis of the kinetics of their appearance and on their growth-association properties. Seven distinct T cell activation antigens, defined by monoclonal antibodies, were classified as early, intermediate, or late antigens based on their temporal appearance relative to DNA synthesis. Four antigens, the transferrin receptor, the T cell activation antigen Tac, the 4F2 antigen, and the 49.9 antigen were early antigens, whereas the OKT10 antigen appeared at intermediate times and both HLA-DR and antigen 19.2 appeared late. The use of a dye, Hoechst 33342, which stains DNA stoichiometrically, allowed the simultaneous analysis of immunofluorescence and cell cycle position of individual cells. This analysis unexpectedly revealed that essentially all cells in the proliferative phase of the cell cycle expressed each of the four early-activation antigens. The correlation between expression of the four early-activation antigens and T cell proliferation suggests that these molecules are important for the growth of all T cells. The relationship of two of these activation antigens, known to be the receptors for transferrin and interleukin 2, a T cell growth factor, is discussed with special reference to the roles of their ligands in supporting the growth of T cells.

scholarly journals Modulation of in vitro and in vivo T-cell responses by transferrin- gallium and gallium nitrate

Blood ◽  
1996 ◽  
Vol 88 (8) ◽  
pp. 3056-3064 ◽  
Author(s):  
WR Drobyski ◽  
R Ul-Haq ◽  
D Majewski ◽  
CR Chitambar
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
Flow Cytometric Analysis ◽  
Immune Reactivity ◽  
Gallium Nitrate ◽  
Slight Reduction ◽  
Killer Activity

Gallium is a group IIIa metal that has efficacy in the therapy of malignant disorders such as lymphoma and urothelial tract tumors. Preclinical studies also indicate a role for gallium in autoimmune disorders, suggesting that gallium is able to modulate T-cell immune reactivity. The purpose of this study was to examine the in vitro and in vivo immunomodulatory action of gallium on T-cell function. Since gallium binds to transferrin in vivo, in vitro studies evaluated the effect of transferrin-gallium (Tf-Ga) on human T cells. Tf-Ga inhibited the mitogen-induced proliferative response of peripheral blood mononuclear cells (PBMC) in a dose-dependent fashion. Alloantigen-induced proliferation was also potently suppressed when evaluated in a mixed lymphocyte culture assay. Tf-Ga affected a significant reduction in the density of IL-2 receptors on activated T cells and a slight reduction in the number of CD3+/CD25+ T cells in PHA-stimulated cultures. Neither secretion of interleukin-2 (IL-2) nor the induction of IL-2-stimulated lymphokine-activated killer activity, however, was inhibited by Tf-Ga. Tf-Ga produced significant upregulation of the transferrin receptor (CD71) in T cells as determined by flow cytometric analysis and northern blot assay, but did not affect the percentage of CD3+/ CD71+ T cells after mitogen stimulation. To assess the in vivo effects of gallium on alloreactive T cells, we evaluated the immunosuppressive effect of gallium in a murine model of graft-versus-host disease (GVHD). Administration of gallium significantly prolonged survival in mice undergoing severe GVHD, suggesting that gallium can ameliorate GVH reactivity. Collectively, these data demonstrate that, at clinically achievable concentrations, Tf-Ga potently inhibits T-cell activation and that this immunosuppressive property of gallium may be of adjunctive therapeutic value in the management of disorders characterized by the presence of autoreactive or alloreactive T-cell populations.

scholarly journals Transient expression of interleukin 2 receptors. Consequences for T cell growth.

1983 ◽  
Vol 158 (6) ◽  
pp. 1895-1911 ◽  
Author(s):  
D A Cantrell ◽  
K A Smith
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cell Growth ◽  
Interleukin 2 ◽  
Flow Cytometric Analysis ◽  
Receptor Expression ◽  
T Cell Proliferation ◽  
Immune Stimulation ◽  
T Cell Growth

T lymphocyte mitosis results from the interaction of interleukin 2 (IL-2) with specific receptors that appear only after appropriate immune stimulation. To assess the potential role of IL-2 receptor levels in determining the rate and magnitude of T cell proliferation, the expression of IL-2 receptors by lectin-stimulated human peripheral blood T cells was examined and correlated with T cell growth. Using biosynthetically radiolabeled IL-2 and anti-Tac, a monoclonal antibody that blocks IL-2 receptor binding, IL-2 receptors were found to accumulate slowly and asynchronously among lectin-stimulated T cells and to precede the onset of DNA synthesis. Moreover, a critical threshold of IL-2 receptor density appeared to be required before the commitment to cell cycle progression, as analyzed quantitatively by tritiated thymidine incorporation and flow cytometric analysis of cellular DNA content. Once maximal IL-2 receptor expression occurred, continued proliferation was IL-2 concentration dependent as assessed using homogenous immunoaffinity-purified IL-2. Upon removal of the activating lectin, IL-2 receptor levels progressively declined, and, in parallel, the rate of proliferation diminished. The decay of IL-2 receptors could not be attributed to IL-2-mediated down-regulation. Instead, renewed IL-2 receptor expression was dependent upon the reintroduction of the initial activating signal. Repetitive exposure to lectin resulted in a more rapid reexpression of maximal IL-2 receptor levels, which was then followed by an accelerated resumption of proliferation. Thus, the extent of T cell proliferation after immune stimulation depends upon the interplay of the IL-2 concentration available and the density of IL-2 receptors expressed, both of which are ultimately determined by antigen/lectin stimulation. The awareness of the transience and the antigen/lectin dependence of IL-2 receptor expression, together with the capacity to monitor T cell cultures for IL-2 receptor levels, should facilitate the initiation and maintenance of cloned, antigen-specific T cells in long-term culture. In addition, these findings suggest that, in vivo, the rapidity of acquisition of maximum IL-2 receptor levels by activated T cells and the duration of IL-2 receptor expression may well direct the magnitude of T cell clonal expansion and resultant immune responses.

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