Depletion of Dendritic Cells Enhances Susceptibility to Cell-Free Infection of Human T Cell Leukemia Virus Type 1 in CD11c-Diphtheria Toxin Receptor Transgenic Mice

Abstract

Human T cell leukemia virus type 1 (HTLV-1) is associated with two immunologically distinct diseases: HTLV-1–associated myelopathy/tropical spastic paraparesis and adult T cell leukemia. The genesis of these diseases is believed to be associated with the route (mucosa versus blood) and mode (cell-free versus cell-associated) of primary infection as well as the modulation of dendritic cell (DC) functions. To explore the role of DCs during early HTLV-1 infection in vivo, we used a chimeric HTLV-1 with a replaced envelope gene from Moloney murine leukemia virus to allow HTLV-1 to fuse with murine cells, which are generally not susceptible to infection with human retroviruses. We also used a CD11c-diphtheria toxin receptor transgenic mouse model system that permits conditional transient depletion of CD11c+ DCs. We infected these transgenic mice with HTLV-1 using both cell-free and cell-associated infection routes in the absence and presence of DCs. The ablation of DCs led to an enhanced susceptibility to infection with cell-free but not cell-associated HTLV-1 in both CD4 and non-CD4 fractions, as measured by the proviral load. Infection with cell-free virus in the absence of DCs was also found to have increased levels of Tax mRNA in the non-CD4 fraction. Moreover, depletion of DCs significantly dampened the cellular immune response (IFN-γ+CD8+ T cells) against both cell-free and cell-associated virus. These results uniquely differentiate the involvement of DCs in early cell-free versus late cell-associated infection of HTLV-1 and highlight a significant aspect of viral immunopathogenesis related to the progression of adult T cell leukemia and HTLV-1–associated myelopathy/tropical spastic paraparesis after the initial infection.

In vivo immunogenicity of Tax(11–19) epitope in HLA-A2/DTR transgenic mice: Implication for dendritic cell-based anti-HTLV-1 vaccine

“…1B). As expected, most of the splenic DC population was ablated within 24 h of DT injection and was reduced to an average of 1.3% as compared with 5.5% of total CD8 + splenocytes in the non-DT control group, as previously observed [36]. Similarly, the reduction in DC frequency slowly recovered by day 5 (data not shown), making it essential to complete the subsequent immunization studies within a 5-day interval.…”

“…The dose, timing, and route of DT administration were implemented as previously described [36]. In vivo depletion of conventional murine splenic DCs from hybrid mice were confirmed by assessing the frequency of CD8α + /CD11c + cells before and after DT treatment (Fig.…”

“…Once it was clear that immunization with Tax(11-19) peptide led to an efficient in vivo priming in HLA-A2.1/DTR mice, the specificity of this response was determined using PE-conjugated Tax(11-19) pentamer that has been well characterized in our previous studies [36]. In addition, pentamer staining was used on control samples to validate the specificity as well as gating for the antigen-specific T-cells.…”

“…1A). Subsequently, a colony of mice positive for both HLA-A2.1 and DTR transgenes was maintained with depletion of splenic DCs achieved using a previously defined dose of DT [36] (Fig. 1B).…”

“…DC priming in early stages of HTLV-1 infection has also been shown to be important for controlling disease progression [36]. To prove this, we had previously used a CD11c-diphtheria toxin receptor (DTR) transgenic mouse model [37, 38] that permits conditional transient depletion of CD11c + DCs.…”