FOXP3+CD25- Tumor Cells with Regulatory Function in Sezary Syndrome

Cutaneous T-cell lymphoma (CTCL) has been suggested by in vitro experiments to represent a malignant CD4(+) T-cell proliferation with a regulatory T-cell (Treg) phenotype (CD4(+)CD25(+)FOXP3(+)). We investigated percentages of FOXP3(+) and CD25(+) cells in the blood of 15 Sezary, 14 mycosis fungoides (MF), and 10 psoriasis (Pso) patients and 20 normal healthy donors (NHDs). We found similar numbers of FOXP3(+) cells in MF (10.4% of blood CD4(+) cells) and Pso (11.1%) patients and NHDs (9.8%). In 8 of 15 (53%) Sezary patients, significantly reduced percentages of FOXP3(+) cells were seen in blood (2.9%) and skin (10.4%). Interestingly, 6 of 15 (40%) Sezary patients showed significantly increased percentages of FOXP3(+) cells (39.7% (blood), 20.3% (skin)); however, these cells did not express CD25. In these latter patients, clone-specific TCR-V beta-chain antibodies were used to demonstrate that these FOXP3(+) CD25(-) cells were monoclonal CTCL tumor cells. FOXP3(+)CD25(-)CTCL tumor cells showed a highly demethylated status of the foxp3 gene locus similar to Treg cells, and they were functionally able to suppress IL-2 mRNA induction in TCR-stimulated conventional T cells. Thus, FOXP3(+)CD25(-)CTCL tumor cells with functional features of Treg cells define a subgroup of Sezary patients who might carry a different prognosis and might require differential treatment.