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Blood, 1 April 2007, Vol. 109, No. 7, pp. 2871-2877.
Prepublished online as a Blood First Edition Paper on December 12, 2006; DOI 10.1182/blood-2006-07-036863.
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IMMUNOBIOLOGY
Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25– into CD25+ T regulatory cells
Antonio Curti1,
Simona Pandolfi1,
Barbara Valzasina2,
Michela Aluigi1,
Alessandro Isidori1,
Elisa Ferri1,
Valentina Salvestrini1,
Giuseppina Bonanno3,
Sergio Rutella3,
Ilaria Durelli4,
Alberto L. Horenstein4,
Francesca Fiore5,
Massimo Massaia5,
Mario P. Colombo2,
Michele Baccarani1, and
Roberto M. Lemoli1
1 Institute of Hematology and Medical Oncology "L. & A. Seràgnoli," University of Bologna and Stem Cell Center, S. Orsola-Malpighi Hospital, Bologna, Italy;
2 Immunotherapy and Gene Therapy Unit, National Cancer Center, Milan, Italy;
3 Department of Hematology, Catholic University Medical School, Rome, Italy;
4 Department of Genetics, Biology and Biochemistry, Research Center on Experimental Medicine (CeRMS), University of Turin, Italy;
5 Hematology Unit, University of Turin and Hematological Oncology Laboratory, CeRMS, Turin, Italy.
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 CD4+CD25+FOXP3+ 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 CD4+CD25+ 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 IDO+AML cells results in the conversion of CD4+CD25– into CD4+CD25+ 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 CD4+CD25– T cells; this effect is counteracted by 1-MT treatment. These data indicate that AML cells induce T-cell tolerance by directly converting CD4+CD25– T cells into CD4+CD25+ Treg cells through an IDO-dependent mechanism.
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