Role of Neuronal Interferon-γ in the Development of Myelopathy in Rats Infected with Human T-Cell Leukemia Virus Type 1

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of not only adult T-cell leukemia but also HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Among the rat strains infected with HTLV-1, chronic progressive myelopathy, named HAM rat disease, occurs exclusively in WKAH rats. In the present study, we found that HTLV-1 infection induces interferon (IFN)-γ production in the spinal cords of HAM-resistant strains but not in those of WKAH rats. Neurons were the major cells that produced IFN-γ in HTLV-1-infected, HAM-resistant strains. Administration of IFN-γ suppressed expression of pX, the gene critically involved in the onset of HAM rat disease, in an HTLV-1-immortalized rat T-cell line, indicating that IFN-γ protects against the development of HAM rat disease. The inability of WKAH spinal cord neurons to produce IFN-γ after infection appeared to stem from defects in signaling through the interleukin (IL)-12 receptor. Specifically, WKAH-derived spinal cord cells were unable to up-regulate the IL-12 receptor β2 gene in response to IL-12 stimulation. We suggest that the failure of spinal cord neurons to produce IFN-γ through the IL-12 pathway is involved in the development of HAM rat disease.