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Tumor necrosis factor-alpha regulates the expression of inducible costimulator receptor ligand on CD34+ progenitor cells during differentiation into antigen presenting cells

Item Type:Article
Title:Tumor necrosis factor-alpha regulates the expression of inducible costimulator receptor ligand on CD34+ progenitor cells during differentiation into antigen presenting cells
Creators Name:Richter, G. and Hayden-Ledbetter, M. and Irgang, M. and Ledbetter, J.A. and Westermann, J. and Koerner, I. and Daemen, K. and Clark, E.A. and Aicher, A. and Pezzutto, A.
Abstract:The inducible costimulator receptor (ICOS) is a third member of the CD28 receptor family that regulates T cell activation and function. ICOS binds to a newly identified ligand on antigen presenting cells different from the CD152 ligands CD80 and CD86. We used soluble ICOSIg and a newly developed murine anti-human ICOS ligand (ICOSL) monoclonal antibody to further characterize the ICOSL during ontogeny of antigen presenting cells. In a previous study, we found that ICOSL is expressed on monocytes, dendritic cells, and B cells. To define when ICOSL is first expressed on myeloid antigen presenting cells, we examined ICOSL expression on CD34+ cells in bone marrow. We found that CD34bright cells regardless of their myeloid commitment were ICOSL-, whereas ICOSL was first expressed when CD34 expression diminished and the myeloid marker CD33 appeared. However, acute myeloid leukemia cells were ICOSL-negative, whereas among B-cell malignancies only some cases of the most mature tumors such as prolymphocytic leukemia and hairy cell leukemia were positive. Next, we investigated purified CD34+ hematopoietic progenitor cells that did not constitutively express ICOSL but were induced to express ICOSL within 12 h after granulocyte/macrophage colony-stimulating factor/tumor necrosis factor {alpha} (TNF-{alpha}) stimulation. Interestingly, ICOSL was induced prior to CD80/CD86 induction on CD34+ cells so that ICOSL was expressed in the absence of CD80/CD86. This suggests that ICOSL is an early differentiation marker along the monocytic/dendritic maturation pathway. Induction of ICOSL was dependent on TNF-{alpha} and was regulated via NF-κB as revealed by use of inhibitors specific for IκBα phosphorylation such as BAY 11-7082 and BAY 11-7085. The antigen presenting capacity of TNF-{alpha} stimulated CD34 + cells was strongly inhibited by ICOSIg fusion proteins or by NF-κB inhibition. Thus, TNF-{alpha}-induced ICOSL expression seemed to be functionally important for the costimulatory capacity of CD34+ hematopoietic progenitor cells.
Keywords:CD34 Antigens, Base Sequence, Cell Differentiation, Dendritic Cells, DNA Primers, Gene Expression Regulation, Hematopoietic Stem Cells, Ligands, Tumor Necrosis Factor, U937 Cells
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology (U.S.A.)
Volume:276
Number:49
Page Range:45686-45693
Date:1 January 2001
PubMed:View item in PubMed

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