scholarly journals DC-SIGN Mediates Cell-Free Infection and Transmission of Human T-Cell Lymphotropic Virus Type 1 by Dendritic Cells

2009 ◽  
Vol 83 (21) ◽  
pp. 10908-10921 ◽  
Author(s):  
Pooja Jain ◽  
Sharrón L. Manuel ◽  
Zafar K. Khan ◽  
Jaya Ahuja ◽  
Kevin Quann ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Lines ◽  
Glut 1 ◽  
Viral Binding ◽  
Human T Cell

ABSTRACT Despite the susceptibility of dendritic cells (DCs) to human T-cell lymphotropic virus type 1 (HTLV-1) infection and the defined role of these cells in disease pathogenesis, the mechanisms of viral binding to DCs have not been fully delineated. Recently, a glucose transporter, GLUT-1, heparan sulfate proteoglycans (HSPGs), and neuropilin-1 (NRP-1) were demonstrated to facilitate HTLV-1 entry into T cells. DCs express their own array of antigen receptors, the most important being the DC-specific intercellular adhesion molecule-3 (ICAM-3)-grabbing nonintegrin (DC-SIGN) with respect to retrovirus binding. Consequently, the role of DC-SIGN and other HTLV-1 attachment factors was analyzed in viral binding, transmission, and productive infection using monocyte-derived DCs (MDDCs), blood myeloid DCs, and B-cell lines expressing DC-SIGN. The relative expression of DC-SIGN, GLUT-1, HSPGs, and NRP-1 first was examined on both DCs and B-cell lines. Although the inhibition of these molecules reduced viral binding, HTLV-1 transmission from DCs to T cells was mediated primarily by DC-SIGN. DC-SIGN also was shown to play a role in the infection of MDDCs as well as model B-cell lines. The HTLV-1 infection of MDDCs also was achieved in blood myeloid DCs following the enhancement of virus-induced interleukin-4 production and subsequent DC-SIGN expression in this cell population. This study represents the first comprehensive analysis of potential HTLV-1 receptors on DCs and strongly suggests that DC-SIGN plays a critical role in HTLV-1 binding, transmission, and infection, thereby providing an attractive target for the development of antiretroviral therapeutics and microbicides.

scholarly journals Activation of hypoxia-inducible factor 1 in human T-cell leukaemia virus type 1-infected cell lines and primary adult T-cell leukaemia cells

2007 ◽  
Vol 406 (2) ◽  
pp. 317-323 ◽  
Author(s):  
Mariko Tomita ◽  
Gregg L. Semenza ◽  
Canine Michiels ◽  
Takehiro Matsuda ◽  
Jun-Nosuke Uchihara ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protein Expression ◽  
Cell Lines ◽  
Transcriptional Activity ◽  
Cell Leukaemia ◽  
Leukaemia Virus ◽  
Human T Cell ◽  
T Cell Lines

HTLV-1 (human T-cell leukaemia virus type 1) is the causative agent for ATL (adult T-cell leukaemia). HTLV-1 Tax can activate the PI3K (phosphoinositide 3-kinase)/Akt signalling pathway, which is responsible for survival of HTLV-1-infected T-cells. HIFs (hypoxia-inducible factors) are transcriptional regulators that play a central role in the response to hypoxia. Overexpression of HIF-1α in many cancers is associated with a poor response to treatment and increased patient mortality. Our objectives in the present study were to investigate whether HIF-1 was activated in HTLV-1-infected T-cells and to elucidate the molecular mechanisms of HIF-1 activation by focusing on the PI3K/Akt signalling pathway. We detected a potent pathway that activated HIF-1 in the HTLV-1-infected T-cells under a normal oxygen concentration. Enhanced HIF-1α protein expression and HIF-1 DNA-binding activity were exhibited in HTLV-1-infected T-cell lines. Knockdown of HIF-1α by siRNA (small interfering RNA) suppressed the growth and VEGF (vascular endothelial growth factor) expression of the HTLV-1-infected T-cell line. HIF-1 protein accumulation and transcriptional activity were enhanced by Tax, which was inhibited by dominant-negative Akt. Importantly, mutant forms of Tax that are defective in activation of the PI3K/Akt pathway failed to induce HIF-1 transcriptional activity. The PI3K inhibitor LY294002 suppressed HIF-1α protein expression, HIF-1 DNA-binding and HIF-1 transcriptional activity in HTLV-1-infected T-cell lines. In primary ATL cells, HIF-1α protein levels were strongly correlated with levels of phosphorylated Akt. The results of the present study suggest that PI3K/Akt activation induced by Tax leads to activation of HIF-1. As HIF-1 plays a major role in tumour progression, it may represent a molecular target for the development of novel ATL therapeutics.

scholarly journals Proliferation Response to Interleukin-2 and Jak/Stat Activation of T Cells Immortalized by Human T-Cell Lymphotropic Virus Type 1 Is Independent of Open Reading Frame I Expression

1999 ◽  
Vol 73 (11) ◽  
pp. 9642-9649 ◽  
Author(s):  
Nathaniel D. Collins ◽  
Celine D’Souza ◽  
Björn Albrecht ◽  
Michael D. Robek ◽  
Lee Ratner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Virus Type ◽  
Interleukin 2 ◽  
Receptor Expression ◽  
Open Reading Frame ◽  
Reading Frame ◽  
Human T Cell

ABSTRACT Human T-cell lymphotropic virus type 1 (HTLV-1), a complex retrovirus, encodes a hydrophobic 12-kD protein from pX open reading frame (ORF) I that localizes to cellular endomembranes and contains four minimal SH3 binding motifs (PXXP). We have demonstrated the importance of ORF I expression in the establishment of infection and hypothesize that p12I has a role in T-cell activation. In this study, we tested interleukin-2 (IL-2) receptor expression, IL-2-mediated proliferation, and Jak/Stat activation in T-cell lines immortalized with either wild-type or ORF I mutant clones of HTLV-1. All cell lines exhibited typical patterns of T-cell markers and maintained mutation fidelity. No significant differences between cell lines were observed in IL-2 receptor chain (α, β, or γc) expression, in IL-2-mediated proliferation, or in IL-2-induced phosphorylated forms of Stat3, Stat5, Jak1, or Jak3. The expression of ORF I is more likely to play a role in early HTLV-1 infection, such as in the activation of quiescent T cells in vivo.

scholarly journals The role of dendritic cells for therapy of B-cell lymphoma with immune checkpoint inhibitors

2020 ◽  
Author(s):  
Anne Scheuerpflug ◽  
Fatima Ahmetlić ◽  
Vera Bauer ◽  
Tanja Riedel ◽  
Martin Röcken ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cell ◽  
Immune Checkpoint ◽  
Cell Lymphoma ◽  
T Cell Responses ◽  
B Cell Lymphoma ◽  
Cell Responses

Abstract Immune checkpoint blocking (ICB) is a promising new tool of cancer treatment. Yet, the underlying therapeutic mechanisms are not fully understood. Here we investigated the role of dendritic cells (DCs) for the therapeutic effect of ICB in a λ-MYC-transgenic mouse model of endogenously arising B-cell lymphoma. The growth of these tumors can be effectively delayed by antibodies against CTLA-4 and PD-1. Tumor-infiltrating DCs from mice having received therapy showed an upregulation of costimulatory molecules as well as an augmented IL-12/IL-10 ratio as compared to untreated controls. Both alterations seemed to be induced by interferon-γ (IFN-γ), which is upregulated in T cells and natural killer cells upon ICB. Furthermore, the enhanced IL-12/IL-10 ratio, which favors Th1-prone antitumor T-cell responses, was a consequence of direct interaction of ICB antibodies with DCs. Importantly, the capability of tumor-infiltrating DCs of stimulating peptide-specific or allogeneic T-cell responses in vitro was improved when DCs were derived from ICB-treated mice. The data indicate that ICB therapy is not only effective by directly activating T cells, but also by triggering a complex network, in which DCs play a pivotal role at the interface between innate and adaptive antitumor responses.

scholarly journals Human T-Cell Lymphotropic Virus Type 1 p12I Expression Increases Cytoplasmic Calcium To Enhance the Activation of Nuclear Factor of Activated T Cells

2002 ◽  
Vol 76 (20) ◽  
pp. 10374-10382 ◽  
Author(s):  
Wei Ding ◽  
Björn Albrecht ◽  
Robert E. Kelley ◽  
Natarajan Muthusamy ◽  
Seung-Jae Kim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Calcium Release ◽  
Nuclear Factor ◽  
Cytoplasmic Calcium ◽  
Activated T Cells ◽  
Human T Cell ◽  
Nfat Activation

ABSTRACT Human T-cell lymphotropic virus type 1 (HTLV-1) establishes persistent infection and is associated with lymphoproliferative or neurodegenerative diseases. As a complex retrovirus, HTLV-1 contains typical structural and enzymatic genes, as well as regulatory and accessory genes encoded in the pX region. The early events necessary for HTLV-1 to establish infection in lymphocytes, its primary target cells, remain unresolved. Recent studies have demonstrated the importance of regulatory and accessory gene products in determining this virus-host interaction. Among these, pX open reading frame I, which encodes two proteins, p12I and p27I, is required for establishing persistent infection in vivo and for infection in quiescent primary lymphocytes. In addition, p12I localizes in the endoplasmic reticulum (ER) and cis-Golgi apparatus and associates with a calcium binding protein, calreticulin. We recently reported that p12I expression induces the calcium-responsive T-cell transcription factor, nuclear factor of activated T cells (NFAT), in the presence of phorbol ester activation. Based on these studies, we hypothesize that p12I may modulate calcium release from the ER. Here, we report that p12I expression increases basal cytoplasmic calcium and concurrently diminishes calcium available for release from the ER stores. Overexpression of calreticulin, a calcium buffer protein, blocked p12I-mediated NFAT activation independently of its ability to bind p12I. Chemical inhibition studies using inhibitors of inositol 1,4,5-triphosphate receptor and calcium release-activated calcium channels suggest that inositol 1,4,5-triphosphate receptor in the ER membrane and calcium release-activated calcium channels in the plasma membrane contribute to p12I-mediated NFAT activation. Collectively, our results are the first to demonstrate the role of p12I in elevating cytoplasmic calcium, an antecedent to T-cell activation, and further support the important role of this accessory protein in the early events of HTLV-1 infection.

scholarly journals Human T-Cell Lymphotropic/Leukemia Virus Type 1 Tax Abrogates p53-Induced Cell Cycle Arrest and Apoptosis through Its CREB/ATF Functional Domain

1998 ◽  
Vol 72 (11) ◽  
pp. 8852-8860 ◽  
Author(s):  
J. C. Mulloy ◽  
T. Kislyakova ◽  
A. Cereseto ◽  
L. Casareto ◽  
A. LoMonico ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Virus Type ◽  
Leukemia Virus ◽  
Functional Domain ◽  
Human T Cell ◽  
Cell Immortalization

ABSTRACT Human T-cell lymphotropic/leukemia virus type 1 (HTLV-1) transforms human T cells in vitro, and Tax, a potent transactivator of viral and cellular genes, plays a key role in cell immortalization. Tax activity is mediated by interaction with cellular transcription factors including members of the CREB/ATF family, the NF-κB/c-Rel family, serum response factor, and the coactivators CREB binding protein-p300. Although p53 is usually not mutated in HTLV-1-infected T cells, its half-life is increased and its function is impaired. Here we report that transient coexpression of p53 and Tax results in the suppression of p53 transcriptional activity. Expression of Tax abrogates p53-induced G1 arrest in the Calu-6 cell line and prevents the apoptosis induced by overexpressing p53 in the HeLa/Tat cell line. The Tax mutants M22 and G148V, which selectively activate the CREB/ATF pathway, exert these same biological effects on p53 function. In contrast, the NF-κB-active Tax mutant M47 has no effect on p53 activity in any of these systems. Consistent with the negative effect of Tax on p53, no activity on a p53-responsive promoter was observed upon transfection of HTLV-1-infected T-cell lines. The p53 protein is expressed at high levels in the nucleus, and nuclear extracts of HTLV-1-infected T cells bind constitutively to a DNA oligonucleotide containing the p53 response element, indicating that Tax does not interfere with p53 binding to DNA. Tax is able to suppress the transactivation function of p53 in three different cell lines, and this suppression required Tax-mediated activation of the CREB/ATF, but not the NF-κB/c-Rel, pathway. Tax and the active Tax mutants were able to abrogate the G1 arrest and apoptosis induced by p53, and this effect does not correlate with an altered localization of nuclear p53 or with the disruption of p53-DNA complexes. The suppression of p53 activity by Tax could be important in T-cell immortalization induced by HTLV-1.

scholarly journals Dendritic Cells Promote the Spread of Human T-Cell Leukemia Virus Type 1 via Bidirectional Interactions with CD4+ T Cells

2019 ◽  
Vol 139 (1) ◽  
pp. 157-166 ◽  
Author(s):  
Takatoshi Shimauchi ◽  
Stephan Caucheteux ◽  
Katja Finsterbusch ◽  
Jocelyn Turpin ◽  
Fabien Blanchet ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Leukemia Virus ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus ◽  
Bidirectional Interactions

scholarly journals Human T-Cell Leukemia Virus Type 1 (HTLV-1) and HTLV-2 Use Different Receptor Complexes To Enter T Cells

2006 ◽  
Vol 80 (17) ◽  
pp. 8291-8302 ◽  
Author(s):  
Kathryn S. Jones ◽  
Kazunori Fugo ◽  
Cari Petrow-Sadowski ◽  
Ying Huang ◽  
Daniel C. Bertolette ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Entry ◽  
Leukemia Virus ◽  
Primary Target ◽  
Cell Leukemia Virus Type ◽  
Glut 1 ◽  
Human T Cell ◽  
T Cell Leukemia Virus

ABSTRACT Studies using adherent cell lines have shown that glucose transporter-1 (GLUT-1) can function as a receptor for human T-cell leukemia virus type 1 (HTLV). In primary CD4+ T cells, heparan sulfate proteoglycans (HSPGs) are required for efficient entry of HTLV-1. Here, the roles of HSPGs and GLUT-1 in HTLV-1 and HTLV-2 Env-mediated binding and entry into primary T cells were studied. Examination of the cell surface of activated primary T cells revealed that CD4+ T cells, the primary target of HTLV-1, expressed significantly higher levels of HSPGs than CD8+ T cells. Conversely, CD8+ T cells, the primary target of HTLV-2, expressed GLUT-1 at dramatically higher levels than CD4+ T cells. Under these conditions, the HTLV-2 surface glycoprotein (SU) binding and viral entry were markedly higher on CD8+ T cells while HTLV-1 SU binding and viral entry were higher on CD4+ T cells. Binding studies with HTLV-1/HTLV-2 SU recombinants showed that preferential binding to CD4+ T cells expressing high levels of HSPGs mapped to the C-terminal portion of SU. Transfection studies revealed that overexpression of GLUT-1 in CD4+ T cells increased HTLV-2 entry, while expression of HSPGs on CD8+ T cells increased entry of HTLV-1. These studies demonstrate that HTLV-1 and HTLV-2 differ in their T-cell entry requirements and suggest that the differences in the in vitro cellular tropism for transformation and in vivo pathobiology of these viruses reflect different interactions between their Env proteins and molecules on CD4+ and CD8+ T cells involved in entry.

The Role of Human T-Lymphotropic Virus Type 1 (HTLV-1)-Infected Dendritic Cells in the Development of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis

1999 ◽  
Vol 73 (6) ◽  
pp. 4575-4581 ◽  
Author(s):  
Masahiko Makino ◽  
Satoshi Shimokubo ◽  
Shin-Ichi Wakamatsu ◽  
Shuji Izumo ◽  
Masanori Baba
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Virus Type ◽  
Spastic Paraparesis ◽  
Tropical Spastic Paraparesis ◽  
Normal Donor ◽  
Dependent Manner ◽  
T Lymphotropic Virus

ABSTRACT The development of human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is closely associated with the activation of T cells which are HTLV-1 specific but may cross-react with neural antigens (Ags). Immature dendritic cells (DCs), differentiated from normal donor monocytes by using recombinant granulocyte-macrophage colony-stimulating factor and recombinant interleukin-4, were pulsed with HTLV-1 in vitro. The pulsed DCs contained HTLV-1 proviral DNA and expressed HTLV-1 Gag Ag on their surface 6 days after infection. The DCs matured by lipopolysaccharides stimulated autologous CD4+ T cells and CD8+ T cells in a viral dose-dependent manner. However, the proliferation level of CD4+ T cells was five- to sixfold higher than that of CD8+ T cells. In contrast to virus-infected DCs, DCs pulsed with heat-inactivated virions activated only CD4+ T cells. To clarify the role of DCs in HAM/TSP development, monocytes from patients were cultured for 4 days in the presence of the cytokines. The expression of CD86 Ag on DCs was higher and that of CD1a Ag was more down-regulated than in DCs generated from normal monocytes. DCs from two of five patients expressed HTLV-1 Gag Ag. Furthermore, both CD4+ and CD8+ T cells from the patients were greatly stimulated by contact with autologous DCs pulsed with inactivated viral Ag as well as HTLV-1-infected DCs. These results suggest that DCs are susceptible to HTLV-1 infection and that their cognate interaction with T cells may contribute to the development of HAM/TSP.

scholarly journals Epiligrin, a component of epithelial basement membranes, is an adhesive ligand for alpha 3 beta 1 positive T lymphocytes.

1993 ◽  
Vol 121 (5) ◽  
pp. 1141-1152 ◽  
Author(s):  
E A Wayner ◽  
S G Gil ◽  
G F Murphy ◽  
M S Wilke ◽  
W G Carter
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Basement Membrane ◽  
B Cell ◽  
Cell Lines ◽  
B Cell Lymphoma ◽  
Lymphokine Activated Killer Cells ◽  
Cutaneous Inflammation ◽  
Epidermal Basement Membrane

The cutaneous T cell lymphomas (CTCL), typified by mycosis fungoides, and several chronic T cell mediated dermatoses are characterized by the migration of T lymphocytes into the epidermis (epidermotropism). Alternatively, other types of cutaneous inflammation (malignant cutaneous B cell lymphoma, CBCL, or lymphocytoma cutis, non-malignant T or B cell type) do not show evidence of epidermotropism. This suggests that certain T lymphocyte subpopulations are able to interact with and penetrate the epidermal basement membrane. We show here that T lymphocytes derived from patients with CTCL (HUT 78 or HUT 102 cells), adhere to the detergent-insoluble extracellular matrix prepared from cultured basal keratinocytes (HFK ECM). HUT cell adhesion to HFK ECM was inhibitable with monoclonal antibodies (mAbs) directed to the alpha 3 (P1B5) or beta 1 (P4C10) integrin receptors, and could be up-regulated by an activating anti-beta 1 mAb (P4G11). An inhibitory mAb, P3H9-2, raised against keratinocytes identified epiligrin as the ligand for alpha 3 beta 1 positive T cells in HFK ECM. Interestingly, two lymphocyte populations could be clearly distinguished relative to expression of alpha 3 beta 1 by flow cytometry analysis. Lymphokine activated killer cells, alloreactive cytotoxic T cells and T cells derived from patients with CTCL expressed high levels of alpha 3 beta 1 (alpha 3 beta 1high). Non-adherent peripheral blood mononuclear cells, acute T or B lymphocytic leukemias, or non-cutaneous T or B lymphocyte cell lines expressed low levels of alpha 3 beta 1 (alpha 3 beta 1low). Resting PBL or alpha 3 beta 1low T or B cell lines did not adhere to HFK ECM or purified epiligrin. However, adhesion to epiligrin could be up-regulated by mAbs which activate the beta 1 subunit indicating that alpha 3 beta 1 activity is a function of expression and affinity. In skin derived from patients with graft-vs.-host (GVH) disease, experimentally induced delayed hypersensitivity reactions, and CTCL, the infiltrating T cells could be stained with mAbs to alpha 3 or beta 1 and were localized in close proximity to the epiligrin-containing basement membrane. Infiltrating lymphocytes in malignant cutaneous B disease (CBCL) did not express alpha 3 beta 1 by immunohistochemical techniques and did not associate with the epidermal basement membrane. The present findings clearly define a function for alpha 3 beta 1 in T cells and strongly suggest that alpha 3 beta 1 interaction with epiligrin may be involved in the pathogenesis of cutaneous inflammation.

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