We conclude that ATLL is not a tumor of FoxP3(+) regulatory T cells, and that a population of FoxP3(+) cells distinct from ATLL cells has regulatory functions and may impair the cell-mediated immune response to HTLV-1 in patients with ATLL.
We describe here different features in Foxp3 expression profile between normal and leukemic CD4(+)CD25(+) T cells, using peripheral blood samples from healthy controls (HCs), human T-cell leukemia virus type-1 (HTLV-1)-infected asymptomatic carriers (ACs), patients with adult T-cell leukemia (ATL), and various hematopoietic cell lines.
Previously, we and others have shown that the majority of ATL cases are strongly positive for CCR4, which may explain the frequent skin invasion of ATL.
In this study, we demonstrated that withdrawal of interleukin (IL)-2 from IL-2-dependent ATL cell lines resulted in induction of HTLV-1 mRNA and protein expression, and that viral induction was associated with phosphorylation of the stress kinase p38 and its downstream CREB.
Recent studies demonstrated that FOXP3, which is a master control gene of naturally occurring regulatory T (Treg) cells, is expressed in the tumor cells from a subset of patients with ATLL.
These results indicate that Foxp3 expression is variable in ATL cases and that Foxp3-high ATL cells, which resemble Treg phenotypically as well as functionally, may be involved in immune suppression in ATL.
Collectively, the frequent co-expression of CCR4 and CCR10, the known pair of skin-homing chemokine receptors, may play an important role in ATLL invasion into the skin.
Real-time polymerase chain reaction and immunostaining detected FoxP3 expression in 10 ATLL cases, but was relatively down-regulated compared with Treg from normal subjects.
In addition, we also found a high expression of FoxP3 mRNA and protein, a hallmark of regulatory T cells, in ATLL cells, indicating the possibility that ATLL cells originated from regulatory T cells.
In the presence of peripheral blood mononuclear cells (PBMCs) from healthy adult donors, KM2760 induced CCR4-specific antibody-dependent cellular cytotoxicity (ADCC) against CCR4-positive ATLL cell lines and primary tumor cells obtained from ATLL patients.
HTLV-I transformed T-cell lines and fresh ATL cells are characterized by constitutive activation of the interleukin-2 receptor (IL-2R) signaling pathway however, the mechanism(s) responsible for constitutive IL-2R activation are unknown.
In the presence of peripheral blood mononuclear cells (PBMCs) from healthy adult donors, KM2760 induced CCR4-specific antibody-dependent cellular cytotoxicity (ADCC) against CCR4-positive ATLL cell lines and primary tumor cells obtained from ATLL patients.
We have examined the specific mechanisms underlying the expression and regulation of the IRF-4 transcription factor in HTLV-I-infected cells and have shown that constitutive IRF-4 expression is exclusive to the transformed, leukemic ATL phenotype as opposed to the nonleukemic HTLV-I associated myelopathies/tropical spastic paraparesis (HAM/TSP) phenotype.
All HTLV-1 infected cell lines and ATL patient lymphocytes demonstrated a dramatic decrease in cyclin B1 levels; subsequent analysis of the cyclin B1 promoter identified two sites important in IRF-4 binding and repression of cyclin B1 expression.
We previously demonstrated that interleukin 2 (IL-2) autocrine/paracrine growth in adult T-cell leukaemia (ATL) cells was closely correlated with clinical aggressiveness.