Minocycline modulates antigen-specific CTL activity through inactivation of mononuclear phagocytes in patients with HTLV-I associated neurologic disease

Phenotypic analysis of CD14+ monocytes in HAM/TSP patients demonstrated high expression of CX3CR1 and HLA-DR in CD14lowCD16+ monocytes, compared to healthy normal donors (NDs) and asymptomatic carriers (ACs), and the production of TNF-α and IL-1β in cultured CD14+ cells of HAM/TSP patients. CD14+ cells of HAM/TSP patients also showed acceleration of HTLV-I Tax expression in CD4+ T cells. Minocycline, an inhibitor of activated MPs, decreased TNF-α expression in CD14+ cells and IL-1β release in PBMCs of HAM/TSP patients. Minocycline significantly inhibited spontaneous lymphoproliferation and degranulation/IFN-γ expression in CD8+ T cells of HAM/TSP patients. Treatment of minocycline also inhibited IFN-γ expression in CD8+ T cells of HAM/TSP patients after Tax11-19 stimulation and downregulated MHC class I expression in CD14+ cells.These results demonstrate that minocycline directly inhibits the activated MPs and that the downregulation of MP function can modulate CD8+ T cells function in HAM/TSP patients. It is suggested that activated MPs may be a therapeutic target for clinical intervention in HAM/TSP.The human T cell lymphotropic virus I (HTLV-I) infects 20 million people worldwide of which the majority of infected individuals are asymptomatic carriers (AC) of the virus [1]. However, in a small percentage of infected individuals, HTLV-I is the etiologic agent of adult T cell leukemia/lymphoma (ATL) [2] and a chronic, progressive neurological disease termed HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [3,4]. Patients with HAM/TSP demonstrate high HTLV-I proviral DNA load, high HTLV-I Tax mRNA load, and high virus-specific immune responses, including increased production of inflammatory cytokines and expansion of Tax-specific CD8+ T cells [5-9]. A high frequency of CD4+ T cells is persistently infected and exhibits high expression of Tax protein [10]. These infected cells are responsible for the increased lymphocyte proliferation in patients wi