Modulation of T cell responses in HTLV-1 carriers and in patients with myelopathy associated with HTLV-1

Abstract

Objective: Human T lymphotropic virus-type 1 (HTLV-1) activates the immune system leading to a persistent and exacerbated T-cell response with increased production of IFN-γ and TNF-α. Overproduction of pro-inflammatory cytokines is correlated with the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), although some HTLV-1 carriers also show high levels of these cytokines. In this study, the ability of regulatory cytokines and cytokine antagonists to inhibit spontaneous IFN-γ production was investigated. Method: IFN-γ levels were measured by ELISA before and after addition of cytokines or anti-cytokines. Results: Addition of IL-10 significantly reduced spontaneous IFN-γ synthesis in cell cultures from HTLV-1 carriers, while no differences were observed in HAM/TSP patients. There was also a tendency to decreased IFN-γ levels in cell cultures from HTLV-1 carriers with exogenous addition of TGF-β. In paired analysis, neutralization of IL-2 significantly decreased IFN-γ production in HTLV-1 carriers but not in HAM/TSP patients. Neutralization of IL-15 was less effective than neutralization of IL-2 in modulating IFN-γ production. In HTLV-1 carriers, anti-IL-2 and simultaneous addition of anti-IL-2 and anti-IL-15 decreased IFN-γ synthesis by 46 and 64%, respectively, whereas in patients with HAM/TSP simultaneous neutralization of both anti-cytokines only decrease IFN-γ levels by 27%. Conclusions: Although a large proportion of HTLV-1 carriers produced high levels of pro-inflammatory cytokines similar to those observed in HAM/TSP patients, immune response can be downregulated by cytokines or cytokine antagonists in most HTLV-1 carriers. This modulation can be an important step in the prevention of tissue damage and progression from the HTLV-1 carrier state to HAM/TSP.