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

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.

DC-SIGN Facilitates Fusion of Dendritic Cells with Human T-Cell Leukemia Virus Type 1-Infected Cells

“…In the present study, we show that, after coculture of HTLV-1-infected cell lines with human DCs, viral particles can be detected within DC vacuoles as early as 3 h after contact and infection of DCs can be observed by immunofluorescence. DC infection is compatible with data obtained in vivo, which demonstrate infection of DCs in HTLV-1-infected asymptomatic carriers (12) and in TSP/HAM patients (20,24,25). HTLV-1 infection does not generally occur through cell-free virions, but rather by direct cell-cell transfer between lymphocytes (13), with involvement of cytoskeletal polarization (5).…”

“…In the few papers devoted to the HTLV-1 infection of DCs, contradictory results have been reported. It was shown previously that DCs are susceptible to HTLV-1 infection in vitro (1,25,26), but another report indicated that DCs are not susceptible to HTLV-1 infection (48), as no evidence of virus uptake was observed after coculture with HTLV-1-infected cell lines. In the present study, we show that, after coculture of HTLV-1-infected cell lines with human DCs, viral particles can be detected within DC vacuoles as early as 3 h after contact and infection of DCs can be observed by immunofluorescence.…”

Presentation of human T cell leukemia virus type 1 (HTLV-1) Tax protein by dendritic cells: the underlying mechanism of HTLV-1-associated neuroinflammatory disease

“…This scenario is also consistent with the concept of Tax cross-presentation by DCs. However, a small fraction of blood DCs (0.4 -5%) from HAM/TSP patients was found to be infected with HTLV-1 [48] and was shown to be susceptible to infection in vitro [45,49,50]. Therefore, we found it important to investigate direct presentation of Tax peptides by infected DCs along with the crosspresentation pathway.…”

“…We have shown previously that DCs exhibit maximum binding affinity to cell-free HTLV-1 as compared with other cell types tested [47], indicating that these cells could be the first type interacting with HTLV-1, particularly during mucosal exposure. DCs obtained from patients with HAM/TSP were found to be infected with HTLV-1 [45,48] and can be infected easily in vitro by cell-free [45,49] and cell-associated [50,51] virus. Therefore, it is likely that infected DCs could process and present Tax antigen in the context of MHC class I, leading to the expansion of Tax-specific CD8 ϩ T cells.…”

The combination of IκB kinase β inhibitor and everolimus modulates expression of interleukin‐10 in human T‐cell lymphotropic virus type‐1‐infected T cells

“…The effect of Bay11-7082 and/or everolimus on allostimulatory capacity of DCs Activated DCs derived from healthy volunteers were potent stimulators of T-cell proliferation. 23 We next examined the function of DCs by using allogeneic mixed lymphocyte reactions. Mature DCs isolated from healthy volunteers potently stimulated the proliferation of lymphocytes ( Fig.…”