Adult T‐cell leukemia/lymphoma cells from blood and skin tumors express cytotoxic T lymphocyte‐associated antigen‐4 and Foxp3 but lack suppressor activity toward autologous CD8⁺ T cells

Abstract

Adult T cell leukemia/lymphoma (ATL) cells share the CD4(+)CD25(+) phenotype with regulatory T (Treg) cells. However, it is still controversial whether ATL cells are Treg cells. The aim of the present study was to investigate the Treg nature of ATL cells obtained from peripheral blood and skin tumors in terms of their phenotype and function. By flow cytometry and immunohistochemistry, the expression of the Treg-associated molecule cytotoxic T lymphocyte-associated antigen (CTLA)-4 and Foxp3 was examined in freshly isolated circulating and skin-infiltrating tumor cells from 21 ATL patients with skin eruptions. The expression of CTLA-4 on freshly isolated circulating tumor cells was elevated in two of 15 patients, and Foxp3 was expressed intracytoplasmically at high levels in three of nine patients. In five of the patients examined, skin-infiltrating tumor cells bore variously elevated CTLA-4 with high Foxp3 expression. The potentiality of ATL cells as Treg cells was further addressed by stimulating ATL cells with anti-CD3/CD28 monoclonal antibodies and monitoring CTLA-4 expression. With the stimulation, even CTLA-4-low ATL cells expressed higher levels of CTLA-4 than normal CD4(+)CD25(+) cells. To study function, ATL cells isolated from blood and skin tumors were tested for their ability to suppress the proliferation of autologous CD8(+) T cells stimulated with allogeneic lymphocytes. Despite the expression of CTLA-4 and Foxp3, these tumors were incapable of suppressing the proliferation of autologous CD8(+) T cells. ATL cells are phenotypically Treg cells in at least some patients, but lack immunoregulatory functions, at least toward CD8(+) 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.…”

“…Some studies showed suppressive activity of ATL cells (39,40), but others did not (26). We demonstrated that the TSDR-hypomethylated ATL cells, which showed higher FOXP3 expression, had suppressive function, whereas the TSDRmethylated ATL cells, which had less FOXP3 expression, did not.…”

“…Selective DNA hypomethylation of conserved cytosine-phosphate-guanine (CpG) residues within the FOXP3 locus, termed the Treg-specific demethylated region (TSDR), is important for distinguishing natural Tregs from peripherally induced Tregs and for stabilizing FOXP3 expression in both humans and mice (23,24). Several studies have shown that FOXP3 expression varies among ATL patients (10,25), and that FOXP3-expressing ATL cells are not always suppressive (26). Therefore, we investigated the DNA methylation pattern of the TSDR and its relevance to Treg properties and clinical outcomes in ATL.…”

Effector Regulatory T Cells Reflect the Equilibrium between Antitumor Immunity and Autoimmunity in Adult T-cell Leukemia

“…ATL occurs in about 5% of human T-lymphotropic virus type-1 (HTLV-1) carriers, and most ATL cells express CCR4 (6,7). ATL cells often share the Treg phenotype, i.e., CD3 þ CD4 þ CD25 þ Foxp3 þ (8,9). Although ATL cells may be defined by their expression of CADM1 (10,11), the overlap and differences between Tregs and ATL cells remain unclear.…”

Host Immune System Abnormalities Among Patients with Human T-Lymphotropic Virus Type 1 (HTLV-1) - Associated Disorders

“…Therefore, it has been hypothesized that ATL cells may be derived from Treg cells (Kohno et al, 2005). Interestingly, some ATL cells exhibit immunosuppressive functions similar to those of Treg cells, which may contribute to the cellular immunodeficiency that has been clinically observed in ATL patients (Chen et al, 2006;Kohno et al, 2005;Matsubar et al, 2006); however, some ATL cells lose this regulatory function (Shimauchi et al, 2008).…”