, Volume 7, Issue 3, pp 164-169
Date: 17 Apr 2008

Acute myeloid leukemia cells inhibit the differentiation and maturation of dendritic cells and induce the generation of regulatory T cells

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Abstract

Objective

To investigate the effects of soluble factors secreted by acute myeloid leukemia (AML) cells on the phenotypical and functional properties of DCs derived from normal mononuclear cells.

Methods

Mononuclear cells were cultured with interleukin-4 (IL-4) and granulocyte-macrophage colony-stimulating factor (GM-CSF), in the presence or absence of 24 h culture supernatants from fresh primary AML cells, to generate immature DCs. The maturation of DCs was induced by cytokines IL-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha), and prostaglandin-2 (PGE-2). The phenotypic alterations of DCs and DCs-primed CD4+ T cells were evaluated using flow cytometry. Precursor frequency (PF) was calculated to monitor the allostimulatory effects of DCs on CD4+ and CD8+ T cells.

Results

AML cell supernatant-treated DCs showed significantly lower expression of co-stimulatory molecules CD80 and CD86, and reduced response to cytokines IL-1beta, IL-6, TNF-alpha, and PGE-2. The allostimulatory effects of AML cell supernatant-treated DCs on CD4+ and CD8+ T cells were significantly lower than those of normal mature DCs [PF: (1.8 ± 0.5)% vs. (5.2 ± 1.6)% for CD4+ T cells, (2.1 ± 0.6)% vs. (6.5 ± 2.0)% for CD8+ T cells, P < 0.01]. These AML supernatant-induced DCs could also induce allogeneic CD4+ T cells to differentiate into CD4+CD25high T cells, which had immunophenotyping characteristics of regulatory T cells, i.e. they expressed Foxp3 but not active maker CD69.

Conclusion

This study demonstrates that soluble factors secreted by AML cells can inhibit development and functions of DCs. In addition, AML supernatant-induced DCs can induce the generation of CD4+CD25high T cells from CD4+ T cells, which may be a mechanism of increased prevalence of CD4+CD25high regulatory T cells and immune dysfunction in AML patients.

Supported by grants from the National Outstanding Young Investigator Program (30225038), Anhui Provincial Natural Science Foundation (070413094), Scientific Research Fund of Anhui Provincial Education Department (2006KJ072C) and Science and Technological Fund of Anhui Province for Outstanding Youth.