Abnormally High Levels of Virus-Infected IFN-γ+CCR4+CD4+CD25+ T Cells in a Retrovirus-Associated Neuroinflammatory Disorder

Yoshihisa Yamano,Toshihiko Izumi,Ryoji Fujii,Satoko Aratani,Hidetoshi Fujita,Kusuki Nishioka,Tomoo Sato,Daisuke Hasegawa,Toshihiro Nakajima,Natsumi Araya,Steven Jacobson,Kazuko Azakami,Atae Utsunomiya,Naoko Yagishita

doi:10.1371/journal.pone.0006517

Abstract

BackgroundHuman T-lymphotropic virus type 1 (HTLV-1) is a human retrovirus associated with both HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), which is a chronic neuroinflammatory disease, and adult T-cell leukemia (ATL). The pathogenesis of HAM/TSP is known to be as follows: HTLV-1-infected T cells trigger a hyperimmune response leading to neuroinflammation. However, the HTLV-1-infected T cell subset that plays a major role in the accelerated immune response has not yet been identified.Principal FindingsHere, we demonstrate that CD4+CD25+CCR4+ T cells are the predominant viral reservoir, and their levels are increased in HAM/TSP patients. While CCR4 is known to be selectively expressed on T helper type 2 (Th2), Th17, and regulatory T (Treg) cells in healthy individuals, we demonstrate that IFN-γ production is extraordinarily increased and IL-4, IL-10, IL-17, and Foxp3 expression is decreased in the CD4+CD25+CCR4+ T cells of HAM/TSP patients as compared to those in healthy individuals, and the alteration in function is specific to this cell subtype. Notably, the frequency of IFN-γ-producing CD4+CD25+CCR4+Foxp3− T cells is dramatically increased in HAM/TSP patients, and this was found to be correlated with disease activity and severity.ConclusionsWe have defined a unique T cell subset—IFN-γ+CCR4+CD4+CD25+ T cells—that is abnormally increased and functionally altered in this retrovirus-associated inflammatory disorder of the central nervous system.

Highlights

Human T-lymphotropic virus type 1 (HTLV-1) is a human retrovirus associated with chronic and persistent infection of human T cells
CD4+CD25+CCR4+ T cells are the main reservoir of HTLV-1 and are present in high numbers in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients
To determine whether CCR4 can be used as a cell surface marker to identify HTLV-1-infected T cells in HAM/TSP patients as reported in adult T-cell leukemia (ATL) cells [22], we separated peripheral blood mononuclear cells (PBMCs) from HAM/TSP patients into the following T cell subtypes by FACS sorting: CD4+CD252CCR42, CD4+CD252CCR4+, CD4+CD25+CCR42, and CD4+CD25+CCR4+ (Figure 1A)

Summary

Introduction

Human T-lymphotropic virus type 1 (HTLV-1) is a human retrovirus associated with chronic and persistent infection of human T cells. While the majority of infected individuals remain healthy lifelong asymptomatic carriers, approximately 3–5% develop aggressive mature T-cell malignancy termed adult T-cell leukemia (ATL) and another 0.25–3% develop a chronic neuroinflammatory disease termed HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [1,2,3,4]. We hypothesized [11,12] that these ‘‘pathogenic’’ HTLV-1-infected T cells may trigger chronic hyperimmune responsiveness in HAM/ TSP patients, and they might be an important target for clinical therapeutic interventional strategies. Human T-lymphotropic virus type 1 (HTLV-1) is a human retrovirus associated with both HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), which is a chronic neuroinflammatory disease, and adult T-cell leukemia (ATL). The HTLV-1-infected T cell subset that plays a major role in the accelerated immune response has not yet been identified

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