Article

Use of human antigen presenting cell gene array profiling to examine the effect of human T-cell leukemia virus type 1 Tax on primary human dendritic cells.

Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Center for Molecular Virology and Neuroimmunology, Center for Cancer Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
Journal of NeuroVirology (Impact Factor: 2.85). 03/2006; 12(1):47-59. DOI: 10.1080/13550280600614981
Source: PubMed

ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) is etiologically linked to adult T-cell leukemia and a progressive demyelinating disorder termed HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). One of the most striking features of the immune response in HAM/TSP centers on the expansion of HTLV-1-specific CD8(+) cytotoxic T lymphocyte (CTL) compartment in the peripheral blood and cerebrospinal fluid. More than 90% of the HTLV-1-specific CTLs are directed against the viral Tax (11-19) peptide implying that Tax is available for immune recognition by antigen presenting cells, such as dendritic cells (DCs). DCs obtained from HAM/TSP patients have been shown to be infected with HTLV-1 and exhibit rapid maturation. Therefore, we hypothesized that presentation of Tax peptides by activated DCs to naIve CD8(+) T cells may play an important role in the induction of a Tax-specific CTL response and neurologic dysfunction. In this study, a pathway-specific antigen presenting cell gene array was used to study transcriptional changes induced by exposure of monocyte-derived DCs to extracellular HTLV-1 Tax protein. Approximately 100 genes were differentially expressed including genes encoding toll-like receptors, cell surface receptors, proteins involved in antigen uptake and presentation and adhesion molecules. The differential regulation of chemokines and cytokines characteristic of functional DC activation was also observed by the gene array analyses. Furthermore, the expression pattern of signal transduction genes was also significantly altered. These results have suggested that Tax-mediated DC gene regulation might play a critical role in cellular activation and the mechanisms resulting in HTLV-1-induced disease.

0 Bookmarks
 · 
50 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The immunopathogenic mechanisms underlying human T-cell leukemia virus type 1 (HTLV-1)- mediated diseases such as adult T-cell leukemia (ATL) and HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are not clearly understood. As critical effectors of antiviral immune response, dendritic cells (DCs) are implicated to play an important role in determining the outcome of HTLV-1 infection. However, a complete understanding of their role in any disease pathogenesis requires extensive assessment of the phenotypic and functional state of DCs. To enable this, we developed a polychromatic antibody cocktail comprising key phenotypic and functional markers of DCs and applied it in a patient cohort from the HTLV-1 endemic region, Jamaica, consisted of seronegative controls, asymptomatic carriers (ACs), ATL, and HAM/TSP patients. This ex vivo analyses included two major subsets of blood DCs, myeloid and plasmacytoid (mDCs and pDCs, respectively). The comparative analyses of results demonstrated a decreased pDC frequency in both ATL and HAM/TSP patients as compared to ACs and seronegative controls. Similarly, CD86 expression on both mDCs and pDCs was significantly higher in HAM/TSP (but not ATL) patients compared to ACs. Interestingly, HLA-DR expression was significantly lower on pDCs of patients as compared to carriers; whereas for mDCs, only the HAM/TSP group had significantly lower expression of HLA-DR. Unlike HAM/TSP individuals, ATL individuals had higher HLA-ABC expression on mDCs compared to ACs. Finally, both mDCs and pDCs of HAM/TSP patients had significantly higher expression of the programmed death ligand 1 (PD-L1) compared to ACs. Overall, this study suggests that DCs exhibit differential phenotypic and functional profile between patients (ATL and HAM/TSP) and carriers of HTLV-1 and could provide an important tool to understand HTLV-1 immunopathogenesis during infection and disease.
    AIDS research and human retroviruses 06/2013; · 2.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: It has been over 25 years since the discovery of human T-cell leukemia virus type 1 (HTLV-1); however, the exact sequence of events that occur during primary infection, clinical latency or the development of disease remains unresolved. The advances in molecular virology and neuroimmunology have contributed significantly to our understanding of HTLV-1 pathogenesis, but also uncovered the complexity of the virus–host interaction both in the peripheral blood and the CNS. Here, we overview the general pathologic features of HTLV-1, molecular mechanisms of oncogenic transformation and characteristics of the host immune response during the associated neuroinflammatory process. We also discuss both current and new approaches in the diagnosis and therapy of HTLV-1 associated diseases – adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. Finally, potentially important emerging areas of research that may have an impact on our understanding of the pathogenic mechanism have been briefly introduced.
    Future Virology 01/2007; 2:481-493. · 0.96 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The human immune system is under constant challenge from many viruses, some of which the body is successfully able to clear. Other viruses have evolved to escape the host immune responses and thus persist, leading to the development of chronic diseases. Dendritic cells are professional antigen-presenting cells that play a major role in both innate and adaptive immunity against different pathogens. This review focuses on the interaction of different chronic viruses with dendritic cells and the viruses' ability to exploit this critical cell type to their advantage so as to establish persistence within the host.
    International Reviews Of Immunology 10/2011; 30(5-6):341-65. · 5.73 Impact Factor