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

Yoshimi Enose-Akahata,Unsong Oh,Eiji Matsuura,Yuetsu Tanaka,Steven Jacobson

doi:10.1186/1742-4690-9-16

Abstract

BackgroundThe activation of mononuclear phagocytes (MPs), including monocytes, macrophages and dendritic cells, contributes to central nervous system inflammation in various neurological diseases. In HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), MPs are reservoirs of HTLV-I, and induce proinflammatory cytokines and excess T cell responses. The virus-infected or activated MPs may play a role in immuneregulation and disease progression in patients with HTLV-I-associated neurological diseases.ResultsPhenotypic 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.ConclusionThese 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.

Highlights

The activation of mononuclear phagocytes (MPs), including monocytes, macrophages and dendritic cells, contributes to central nervous system inflammation in various neurological diseases
We demonstrate that CD14+ cells of patients with human T cell lymphotropic virus I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) showed an inflammatory phenotype as evidenced by high expression of HLA-DR and CX3CR1, proinflammatory cytokines (TNF-a and IL-1b) and acceleration of HTLV-I Tax expression in CD4+ T cells
Treatment with minocycline demonstrated inhibition of IFN-g expression in CD8+ T cells of patients with HAM/TSP, resulting from inhibition of MP activation by minocycline. These results demonstrate that CD8+ T cell activation of patients with HAM/TSP can be suppressed through down-regulation of MP activation, and suggest a novel treatment strategy in patients with HTLV-I associated neurological disease

Summary

Introduction

The activation of mononuclear phagocytes (MPs), including monocytes, macrophages and dendritic cells, contributes to central nervous system inflammation in various neurological diseases. High frequency of activated CD8+ T cells in peripheral blood and even higher in cerebrospinal fluid has been reported [12] In addition to these strong HTLV-I-associated T cell responses, it has been suggested that mononuclear phagocytes (MPs; monocytes, dendritic cells, tissue macrophages and microglia) are involved in the pathogenesis of HAM/TSP. Pathological studies have confirmed the presence of inflammatory monocyte/macrophages as well as CD4+ T cells and CD8+ T cells in the central nervous system (CNS) of HAM/TAP patients [20,21] These findings suggest that virus-infected or activated MPs may play a role in immune regulation and disease progression in patients with HTLV-I-associated neurological diseases

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