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

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.

Identification of Human T Cell Leukemia Virus Type 1 Tax Amino Acid Signals and Cellular Factors Involved in Secretion of the Viral Oncoprotein

“…These observations have suggested that Tax is available for immune recognition by antigen-presenting cells. Consistent with this avenue of thought, we have demonstrated that extracellular Tax can induce the expression of several genes involved in activation and maturation of dendritic cells, the most potent antigenpresenting cells (24). We have also demonstrated that Tax alters dendritic cell function and induces T cell proliferation in a mixed lymphocyte culture (25).…”

Retrovirally induced CTL degranulation mediated by IL-15 expression and infection of mononuclear phagocytes in patients with HTLV-I–associated neurologic disease

“…69 In HTLV-I, IL-15 mRNA level are up-regulated in non-T cells isolated from HAM/TSP patients and DC treated with HTLV-I Tax protein in vitro. 70,71 We showed that IL-15 expression was rapidly enhanced on the surface of CD14 ϩ cells in HAM/TSP patients more than those in ACs. In addition, rhIL-15 induced CD107a/ IFN-␥ expression from CD8 ϩ T cells of HTLV-I-infected patients, especially HAM/TSP patients, but not NDs that needed much higher concentrations of IL-15 to induce CD107a/IFN-␥ expression.…”

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

“…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.…”