IFN-γ production in response to Tax 161-233, and frequency of CD4⁺ Foxp3⁺ and Lin⁻ HLA-DRhigh CD123⁺ cells, discriminate HAM/TSP patients from asymptomatic HTLV-1-carriers in a Peruvian population
2009
Best, Ivan | Lopez, Giovanni | Verdonck, Kristien | González, Elsa | Tipismana, Martín | Gotuzzo, Eduardo | Vanham, Guido | Clark, Daniel
Human T-lymphotropic virus 1 (HTLV-1) can cause HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The objective of this study was to gain insight into the pathogenesis of HAM/TSP by focusing on the CD8⁺ T-cell response. Twenty-three HTLV-1-seronegative controls (SC), 29 asymptomatic HTLV-1 carriers (AC) and 48 patients with HAM/TSP were enrolled in the study. We evaluated the production of interferon-γ (IFN-γ) in peripheral blood mononuclear cells stimulated with Tax overlapping peptides, the expression of genes related to the CD8⁺ cytotoxic T-cell response, the frequency of CD4⁺ Foxp3⁺ cells and of dendritic cells, and the HTLV-1 provirus load (PVL). The frequency of cells producing IFN-γ in response to Tax 161-233, but not to Tax 11-19, discriminated patients with HAM/TSP from AC. The increased pro-inflammatory response observed in patients with HAM/TSP was shared by AC with a high PVL, who also exhibited lower levels of granzyme H mRNA in unstimulated CD8⁺ T cells than AC with a low PVL. Patients with HAM/TSP showed higher frequencies of CD4⁺ Foxp3⁺ cells and lower frequencies of plasmacytoid dendritic cells (pDC) than AC. Our findings are consistent with a model in which HTLV-1, along with the host genetic background, drives quantitative and qualitative changes in pDC and CD4⁺ Foxp3⁺ cells that lead to a predominance of inflammatory responses over lytic responses in the CD8⁺ T-cell response of individuals predisposed to develop HAM/TSP.
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