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 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 (T(reg)) 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 T(reg) 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+ T(reg) cells through an IDO-dependent mechanism.
Curti
Antonio
A
Institute of Hematology and Medical Oncology "L. & A. Seràgnoli," University of Bologna and Stem Cell Center, S. Orsola-Malpighi Hospital, Bologna, Italy. acurti@alma.unibo.it
Pandolfi
Simona
S
Valzasina
Barbara
B
Aluigi
Michela
M
Isidori
Alessandro
A
Ferri
Elisa
E
Salvestrini
Valentina
V
Bonanno
Giuseppina
G
Rutella
Sergio
S
Durelli
Ilaria
I
Horenstein
Alberto L
AL
Fiore
Francesca
F
Massaia
Massimo
M
Colombo
Mario P
MP
Baccarani
Michele
M
Lemoli
Roberto M
RM
D000328:Adult; D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D017931:DNA Primers / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism*
D017931:DNA Primers; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053645:Interleukin-2 Receptor alpha Subunit; D014364:Tryptophan