TAX-mRNA-Carrying Exosomes from Human T Cell Lymphotropic Virus Type 1-Infected Cells Can Induce Interferon-Gamma Production In Vitro.

Abstract

Human T cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T cell leukemia/lymphoma. The development of HAM/TSP, a chronic neuroinflammatory disease, is correlated to complex interaction between the host immune response and the infecting virus. Tax expression plays an important role in HAM/TSP pathogenesis by activating various cellular genes, including the cytokines interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Exosomes have emerged as an important factor of cell-to-cell communication contributing to diverse cellular processes, including immune modulation. Considering the potential role of exosomes in modulating the immune response and inflammation, the main objective of this study was to examine if HTLV-1-infected cells produce exosomes carrying viral proteins or inflammatory molecules, which can participate in the chronic inflammation that is observed in patients with HAM/TSP. Exosomes were isolated from HTLV-1-infected cell line, evaluated for the tax mRNA presence, and tested for the ability to activate peripheral mononuclear cells (PBMC) in inducing an inflammatory immune response. We observed that the proinflammatory cytokines, IFN-γ and TNF-α, were upregulated in T cells after treatment of the PBMC with Tax-carrying exosomes compared to the negative control. Interleukin-4, Granzyme B, and Perforin did not show alterations. Taken together, these results suggest that exosomes carrying tax-mRNA isolated from HTLV-1-infected cells might induce the production of proinflammatory cytokines and activate T helper (Th)1, and not Th2-immune response. If this finding is further confirmed, this study may have impact on investigations on the pathogenesis of HAM-TSP and the inflammatory response involved in this disease.