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

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.