Modulation of dendritic cell maturation and function by the Tax protein of human T cell leukemia virus type 1

Abstract

Human T cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is characterized by the generation of an intense CTL cell response directed against the viral transactivator protein Tax. In addition, patients diagnosed with HAM/TSP exhibit rapid activation and maturation of dendritic cells (DC), likely contributing to the robust, Tax-specific CTL response. In this study, extracellular Tax has been shown to induce maturation and functional alterations in human monocyte-derived DC, critical observations being confirmed in freshly isolated myeloid DC. Tax was shown to promote the production of proinflammatory cytokines and chemokines involved in the DC activation process in a dose-and time-dependent manner. Furthermore, Tax induced the expression of DC activation (CD40, CD80, and CD86) and maturation (CD83) markers and enhanced the T cell proliferation capability of DC. Heat inactivation of Tax resulted in abrogation of these effects, indicating a requirement for the native structure of Tax, which was found to bind efficiently to the DC membrane and was internalized within a few hours, suggesting that extracellular Tax may possess an intracellular mechanism of action subsequent to entry. Finally, inhibitors of cellular signaling pathways, NF-κB, protein kinase, tyrosine kinase, and phospholipase C, were shown to inhibit Tax-mediated DC activation. This is the first study reporting the immunomodulatory effects of extracellular Tax in the DC compartment. These results suggest that DC, once exposed to Tax by uptake from the extracellular environment, can undergo activation, providing constant antigen presentation and costimulation to T cells, leading to the intense T cell proliferation and inflammatory responses underlying HAM/TSP.

HIV-1 Tat Protein Induces PD-L1 (B7-H1) Expression on Dendritic Cells through Tumor Necrosis Factor Alpha- and Toll-Like Receptor 4-Mediated Mechanisms

“…Because Tat-MoDC maturation can be blocked in the presence of anti-TNF-␣ and anti-TLR4 antibodies (data not shown), on the one hand, and can be stimulated by the N-terminal 1-45 fragment of Tat, on the other hand, our data suggest that MoDC maturation is primed by Tat action at the cell membrane level rather than following its uptake (37). Interestingly, HTLV-1 Tax protein, the equivalent of Tat protein in HIV-1, also induced MoDC maturation (72). Curiously, the activating effect of Tat protein seems to be counterbalanced by the action of Vpr, another HIV-1 regulatory protein, which has an antagonist effect on the maturation of DCs (73).…”

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

“…A total of 50,000 events collected for each sample were gated to , and 24 h) postinfection, cells were harvested for the isolation of total RNA (Qiagen, Valencia, CA) followed by treatment with DNase (rDNase I; Ambion, Inc., Austin, TX). The reverse transcription reaction was performed with 1 g of total RNA using Omniscript reverse transcriptase (4 U; Qiagen) in the presence of deoxynucleoside triphosphates (0.5 mM each deoxynucleoside triphosphate; Qiagen), oligo(dT) 15 primer (1 M; Promega, Madison, WI), and RNase inhibitor (10 U; Ambion). The kinetics of viral gene expression was examined by real-time PCR (RT-PCR) (ABI Prism 7700; Applied Biosystems, Foster City, CA).…”

“…Moreover, DCs cocultured with an HTLV-1-producing T-cell line were able to stimulate high levels of proliferation in autologous lymphocytes (28), as observed in HAM/TSP patients. HTLV-1 Tax protein also was shown to modulate DC maturation and function (1,2,15). Therefore, the importance of DCs in HTLV-1 pathogenesis is evident with respect to both ATL and HAM/TSP.…”

“…NJ) density gradient centrifugation. Immature MDDCs were generated from purified monocytes in the presence of recombinant human granulocyte-macrophage colony-stimulating factor (100 IU/ml) and IL-4 (300 IU/ml) (both from Peprotech, Inc., Rocky Hill, NJ) as previously described (15). Differentiation to DCs was confirmed by multicolor fluorescence-activated cell sorting (FACS) analyses for MDDC surface markers (HLA-ABC, HLA-DR, CD40, CD80, and CD86) using fluorochrome-conjugated Abs (eBioscience, San Diego, CA) along with a lineage cocktail containing Ab (Lin-1; BD Biosciences, San Jose, CA) to exclude all non-MDDC types.…”

Immunopathogenesis and neurological manifestations associated to HTLV-1 infection

“…DCs are also capable of transmitting the virus to T cells in vitro 41 . Jain et al showed that DCs exposed to the Tax protein become activated, leading to intense T-cell proliferation and inflammation due to their ability to present antigen to naïve T cells 42 . When evaluating the maturation of monocytederived DCs obtained from HTLV-1-infected individuals, Nascimento et al observed that DCs from healthy subjects displayed an activation profile (increased expression of costimulatory molecules and HLA-DR) absent in DCs from HTLV-1-infected patients 20 .…”