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

• Published in: Retrovirology Vol. 9; no. 1; p. 46
• Main Authors: Satou, Yorifumi, Utsunomiya, Atae, Tanabe, Junko, Nakagawa, Masanori, Nosaka, Kisato, Matsuoka, Masao
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 30.05.2012; BioMed Central; BMC
• Subjects: Aged; Analysis; ATL; Carrier State - virology; Case-Control Studies; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - virology; CTLA-4 Antigen - genetics; CTLA-4 Antigen - metabolism; Female; Flow Cytometry; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; FoxP3; Gene expression; Genes, pX; Genetic aspects; Genomes; Genotype & phenotype; Glucocorticoid-Induced TNFR-Related Protein - genetics; Glucocorticoid-Induced TNFR-Related Protein - metabolism; HAM/TSP; HBZ; Health aspects; HTLV-1; HTLV-I (Virus); HTLV-I Infections - virology; Human T-lymphotropic virus 1 - genetics; Human T-lymphotropic virus 1 - pathogenicity; Humans; Immune system; Infection; Leukemia; Leukemia-Lymphoma, Adult T-Cell - metabolism; Leukemia-Lymphoma, Adult T-Cell - virology; Leukocyte Common Antigens - genetics; Leukocyte Common Antigens - metabolism; Lymphocytes; Male; Medical research; Medicine, Experimental; Middle Aged; Normal distribution; Pathogenesis; Phenotype; Physiological aspects; Proteins; Studies; T cells; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - virology; Tax; Viral Load; United Kingdom; Japan
• ISSN: 1742-4690; 1742-4690
• DOI: 10.1186/1742-4690-9-46

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. 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 Treg 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-FoxP3low 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. HTLV-1 infection induces an abnormal frequency and phenotype of FoxP3+CD4+ T cells.