Possible origin of adult T-cell leukemia/lymphoma cells from human T lymphotropic virus type-1-infected regulatory T cells.

Adult T-cell leukemia/lymphoma (ATLL) is a lymphoproliferative disorder caused by human T lymphotropic virus type 1 (HTLV-I). Although ATLL cells display an activated helper/inducer T-cell phenotype, CD4+ and CD25+, they are known to exhibit strong immunosuppressive activity. As regulatory T cells (Treg cells) express CD4+ and CD25+ molecules and possess potent immune response suppressive activity, we investigated a possible link between ATLL cells and Treg cells. In primary ATLL cells, the expression levels of the Treg cell marker molecules Foxp3 and glucocorticoid-induced tumor necrosis factor receptor family related protein (GITR) were significantly higher than in those from healthy adults. Furthermore, ATLL cells are unresponsive in vitro to concanavalin A stimulation and suppress the proliferation of normal T cells. GITR mRNA expression was induced by the HTLV-I transactivator Tax, and GITR promoter analyses revealed that this induction depends on the kappaB site from -431 bp to -444 bp upstream of the putative transcription site. Taken together, ATLL cells may originate from HTLV-I-infected Treg cells, and GITR seems to be involved in the progression to ATLL.