Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25- into CD25+ T regulatory cells

Indoleamine 2,3-dioxygenase (IDO) is a novel immunosuppressive agent expressed in some subsets of normal and neoplastic cells, including acute myeloid leukemia (AML) cells. Here, we show that IDO expression correlates with increased circulating CD4CD25FOXP3 T cells in patients with AML at diagnosis. In vitro, IDO AML cells increase the number of CD4 CD25 T cells expressing surface CTLA-4 and FOXP3 mRNA, and this effect is completely abrogated by the IDO inhibitor, 1-methyl tryptophan (1-MT). Purified CD4CD25 T cells obtained from coculture with IDO AML cells act as T regulatory (Treg) cells because they do not proliferate, do not produce interleukin (IL)‐2, and inhibit naive T-cell proliferation. Coculture with IDOAML cells results in the conversion of CD4CD25 into CD4CD25 T cells, which is completely abrogated by 1-MT. Moreover, in mice, intrasplenic injection of IDO leukemia/ lymphoma A20 cells induces the expansion of bona fide Treg cells by conversion of CD4CD25 T cells; this effect is counteracted by 1-MT treatment. These data indicate thatAML cells induce T-cell tolerance by directly converting CD4CD25 T cells into CD4CD25 Treg cells through an IDO-dependent mechanism. (Blood. 2007;109:2871-2877)