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

Abstract

IntroductionIndoleamine 2,3-dioxygenase (IDO) is a key enzyme in the tryptophan metabolism that catalyzes the initial rate-limiting step of tryptophan degradation along the kynurenine pathway. 1 Tryptophan starvation by IDO consumption inhibits T-cell activation, 1,2 while products of tryptophan catabolism, such as kynurenine derivatives and O 2 -free radicals, regulate T-cell proliferation and survival. 1,3 Thus, IDO has been shown to exert an immunosuppressive activity, and cell populations, including regulatory dendritic cells (DCs) and bone marrow (BM)-derived mesenchymal stem cells (MSCs), expressing IDO have the capacity to suppress T-cell responses to auto-and alloantigens. 4,5 A wide variety of human solid tumors express IDO. 6 More recently, we demonstrated that also acute myeloid leukemia (AML) cells, but not their normal counterparts (ie, CD34 ϩ hematopoietic stem/progenitor cells [HSCs]), express an active IDO protein, which converts tryptophan into kynurenine and inhibits allogeneic T-cell proliferation. 7 Naturally arising CD4 ϩ CD25 ϩ Foxp3 ϩ T regulatory (T reg ) cells are known to suppress most types of immune response, 8,9 including antitumor immunity. [10][11][12][13] IDO is expressed and is functionally active in placenta, which, in turn, is infiltrated by CD4 ϩ CD25 ϩ T reg cells. [14][15][16] Moreover, Candida albicans infection increases the number of T reg cells because of IDO induction in host antigenpresenting cells (APCs). 17 In human cancers, tumor-draining lymph nodes contain IDO-expressing DCs that enhance T reg cell function. 18 These data suggest the close relationship between IDO activity and the occurrence of T reg cells, 19 but the mechanism governing the generation of T reg cells by IDO-expressing tumors is presently unknown.In the present study, we investigated whether the expression of IDO by AML cells may play a direct role in the development of T reg cells. Materials and methods CellsAll human samples were obtained after informed consent was signed, according to institutional guidelines. Approval was obtained from Bologna Hospital Ethical Committee. Buffy coats were obtained from healthy adults during the preparation of transfusion products. BM and/or peripheral blood (PB) samples including at least 70% leukemic cells were harvested from 76 patients with AML at diagnosis. CD3 ϩ and CD4 ϩ cells were purified from the mononuclear cell (MNC) fraction by MiniMacs high-gradient magnetic separation column (Miltenyi Biotec, Bergisch Gladbach, Germany) according to the manufacturer's instructions (purity of CD3 ϩ and CD4 ϩ cell populations was always greater than 95%). MSCs were generated from BM cells as previously reported. 20 Murine A20 and CT26 cell lines were obtained from the American Type Culture Collection (ATCC; Rockville, MD) and maintained in RPMI 1640 (Whittaker Bioproducts, Walkersville, MD) or MEM (Whittaker Bioproducts) supplemented with 10% FCS (Sera Lab, Crawley Down, United The online version of this manuscript contains a data supplement.The publication costs of ...

Expansion of FOXP3+ CD8 T Cells with Suppressive Potential in Colorectal Mucosa Following a Pathogenic Simian Immunodeficiency Virus Infection Correlates with Diminished Antiviral T Cell Response and Viral Control

“…It has been shown that SIV/HIV induces increased expression of IDO, an immunosuppressive enzyme that is capable of inducing CD4 Tregs (58). This increase in IDO expression is detected in lymphoid and intestinal mucosal tissues as early as 7 d after SIV infection (30,31,37,59).…”

High INDO (indoleamine 2,3-dioxygenase) mRNA level in blasts of acute myeloid leukemic patients predicts poor clinical outcome

“…Myeloid leukemic blasts do express an active form of indoleamine 2,3-dioxygenase protein as previously demonstrated in human myeloid leukemic samples and in vivo in mice. 11,12 Moreover, Curti et al demonstrated good correlation between INDO mRNA level, indoleamine 2,3-dioxygenase protein expression levels and function in myeloid leukemic samples.…”

“…11 They also clearly demonstrated that indoleamine 2,3-dioxygenase expressed by human myeloid leukemic cells induces the expansion of CD4 + CD25 + FOXP3 + regulatory T cells in mice. 12 These data presume an important role for indoleamine 2,3-dioxygenase in immune escape. However, negative influence of high indoleamine 2,3-dioxygenase expression on overall survival of patients has only been demonstrated for endometrial and colorectal cancer.…”

Dynamic Behavior and Function of Foxp3+ Regulatory T Cells in Tumor Bearing Host

“…First, tumor antigen specific Foxp3 + Tregs have been isolated from tumor tissues as well as peripheral blood from patients with melanoma and cervical cancer (52)(53)(54). Second, APCs extracted from human leukemia and other cancers can induce Treg conversion from naïve CD4 T cells in vitro (55,56). However, distinguishing aTreg from nTregs remains a major challenge.…”