HTLV-1 modulates the frequency and phenotype of FoxP3+CD4+T cells in virus-infected individuals

Abstract

Background HTLV-1 utilizes CD4 T cells as the main host cell and maintains the proviral load via clonal proliferation of infected CD4 + T cells. Infection of CD4 + T cells by HTLV-1 is therefore thought to play a pivotal role in HTLV-1-related pathogenicity, including leukemia/lymphoma of CD4 + T cells and chronic inflammatory diseases. Recently, it has been reported that a proportion of HTLV-1 infected CD4 + T cells express FoxP3, a master molecule of regulatory T cells. However, crucial questions remain unanswered on the relationship between HTLV-1 infection and FoxP3 expression. Results To investigate the effect of HTLV-1 infection on CD4 + T-cell subsets, we used flow cytometry to analyze the T-cell phenotype and HTLV-1 infection in peripheral mononuclear cells (PBMCs) of four groups of subjects, including 23 HTLV-1-infected asymptomatic carriers (AC), 10 patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), 10 patients with adult T-cell leukemia (ATL), and 10 healthy donors. The frequency of FoxP3 + cells in CD4 + T cells in AC with high proviral load and patients with HAM/TSP or ATL was higher than that in uninfected individuals. The proviral load was positively correlated with the percentage of CD4 + T cells that were FoxP3 + . The CD4 + FoxP3 + T cells, themselves, were frequently infected with HTLV-1. We conclude that FoxP3 + T- cells are disproportionately infected with HTLV-1 during chronic infection. We next focused on PBMCs of HAM/TSP patients. The expression levels of the T reg associated molecules CTLA-4 and GITR were decreased in CD4 + FoxP3 + T cells. Further we characterized FoxP3 + CD4 + T-cell subsets by staining CD45RA and FoxP3, which revealed an increase in CD45RA − FoxP3 low non-suppressive T-cells. These findings can reconcile the inflammatory phenotype of HAM/TSP with the observed increase in frequency of FoxP3 + cells. Finally, we analyzed ATL cells and observed not only a high frequency of FoxP3 expression but also wide variation in FoxP3 expression level among individual cases. Conclusions HTLV-1 infection induces an abnormal frequency and phenotype of FoxP3 + CD4 + T cells.

Hypomethylation of the Treg-Specific Demethylated Region in FOXP3 Is a Hallmark of the Regulatory T-cell Subtype in Adult T-cell Leukemia

“…FOXP3 expression in ATL cell lines and primary ATL cells has been investigated by many researchers at the mRNA and protein levels, and it varies widely among cell lines and individual cases (10,11,25,26,38,39). Our data also showed a wide range of FOXP3 expression among primary ATL cells.…”

HTLV-1 induces a Th1-like state in CD4+CCR4+ T cells

“…There is strong evidence to support the conclusion that a substantial portion of the Treg population in HAM/TSP patients is infected with HTLV-1 (28,29). In a previous study, we demonstrated that CD4…”

Increased Expression of <i>HBZ</i> and <i>Foxp3</i> mRNA in Bronchoalveolar Lavage Cells Taken from Human T-lymphotropic Virus Type 1-associated Lung Disorder Patients

“…Several studies have shown the dysregulation of Foxp3 expression in human inflammatory diseases. In the case of HTLV-I infection, it has been reported that a proportion of the HTLV-I-infected CD4 + T cells express Foxp3, and that HTLV-I infection induces an abnormal frequency and phenotype of Foxp3 + CD4 + T cells in HAM/TSP patients (43). In this study, we found that the high expression levels of Foxp3 mRNAs in the BAL cells tended to positively correlate with the proportion of lymphocytes in the BALF from patients with HTLV-I-associated lung disorders.…”