Evaluating the role of dendritic cells in host immune response during Human T Cell Leukemia Virus Type 1 (HTLV-1) infection using a transgenic mouse model system

Saifur Rahman

doi:10.17918/00009932

Human T-cell leukemia virus type 1 (HTLV-1) is associated with two immunologically distinct diseases: adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The genesis of these diseases is believed to be associated with the route (mucosa versus blood) of primary infection as well as the modulation of host immune response. In this regard, the role of antigen presenting cells, in particular dendritic cells (DCs), is becoming increasingly important. In studies presented herein we closely examined the importance of DCs in controlling early HTLV-1 infection in vivo utilizing a chimeric HTLV-1 with a replaced envelope gene from the Moloney murine leukemia virus to allow HTLV-1 to fuse with murine cells. We also used a CD11c-diphtheria toxin receptor (DTR) transgenic mouse model system that permits conditional transient depletion of CD11c+ DCs. We infected these transgenic mice with HTLV-1 via 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 the CD4 and non-CD4 fractions as measured by the proviral and the expression of viral transactivator protein Tax. We also observed a significantly dampened cellular immune response (assessed by the frequency of IFN-[gamma]+CD8+ T cells) against both cell-free and cell-associated virus in the absence of DCs. To further understand the mechanism of this differential response, we cultured murine bone marrow cells in the presence of FMS-like tyrosine kinase 3 ligand (F1t3L) to generate bone marrow derived DCs (FL-DCs) in vitro. Upon infection with cell-free chimeric HTLV-1 virus, FL-DCs demonstrated an increased expression of MHC class II (but not class I) and costimulatory molecules - CD80 and CD86. The kinetics of viral entry, integration and gene expression was demonstrated using both competent as well as UV irradiated virus. In response to viral insult, FL-DCs produced large amounts of the type 1 interferon (IFN-[alpha]) as well as an array of proinflammatory cytokines. The same observations were made during a productive ongoing infection setup with the replication-competent virus but not with the UV-irradiated virus demonstrating the specificity of the HTLV-1-mediated effects. Gene expression profiling studies demonstrated the upregulation of many interferon-associated genes and their receptors, interferon stimulated genes, signaling molecules as well as genes involved in antigen uptake and presentation. Interestingly, there was a striking downregulation of genes for cytokines, chemokines and their ligands suggesting the plausible role of HTLV-1 to interfere with DC migration. In addition, mixed lymphocyte reaction demonstrated the capacity of the virally activated and matured DCs to proliferate autologous CD3+ T cells. Moreover, these T cells were also able to produce IFN-[gamma] following culture with the productively infected DCs. These results thus uniquely demonstrate the critical role of DCs in their ability to mount both innate and adaptive immune responses during early cell-free HTLV-1 infection and highlight a significant aspect of viral immunopathogenesis related to the progression of ATL and HAM/TSP upon infection.

Evaluating the role of dendritic cells in host immune response during Human T Cell Leukemia Virus Type 1 (HTLV-1) infection using a transgenic mouse model system

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Evaluating the role of dendritic cells in host immune response during Human T Cell Leukemia Virus Type 1 (HTLV-1) infection using a transgenic mouse model system

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