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Blood, 1 December 2006, Vol. 108, No. 12, pp. 3792-3800.
Prepublished online as a Blood First Edition Paper on August 17, 2006; DOI 10.1182/blood-2006-02-004978.
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IMMUNOBIOLOGY
Stimulated plasmacytoid dendritic cells impair human T-cell development
Heike Schmidlin,
Wendy Dontje,
Fedde Groot,
Suzanne J. Ligthart,
Arnaud D. Colantonio,
Monique E. Oud,
Esther J. Schilder-Tol,
Marcel Spaargaren,
Hergen Spits,
Christel H. Uittenbogaart, and
Bianca Blom
From the Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, The Netherlands; Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, The Netherlands; Department of Pathology, Academic Medical Center, University of Amsterdam, The Netherlands; Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California–Los Angeles (UCLA); and Department of Pediatrics, David Geffen School of Medicine, UCLA.
Thymic plasmacytoid dendritic cells (pDCs) are located predominantly in the medulla and at the corticomedullary junction, the entry site of bone marrow–derived multipotential precursor cells into the thymus, allowing for interactions between thymic pDCs and precursor cells. We demonstrate that in vitro–generated pDCs stimulated with CpG or virus impaired the development of human autologous CD34+CD1a– thymic progenitor cells into the T-cell lineage. Rescue by addition of neutralizing type I interferon (IFN) antibodies strongly implies that endogenously produced IFN- / is responsible for this inhibitory effect. Consistent with this notion, we show that exogenously added IFN- had a similar impact on IL-7– and Notch ligand–induced development of thymic CD34+CD1a– progenitor cells into T cells, because induction of CD1a, CD4, CD8, and TCR/CD3 surface expression and rearrangements of TCR V-DJ gene segments were severely impaired. In addition, IL-7–induced proliferation but not survival of the developing thymic progenitor cells was strongly inhibited by IFN-. It is evident from our data that IFN- inhibits the IL-7R signal transduction pathway, although this could not be attributed to interference with either IL-7R proximal (STAT5, Akt/PKB, Erk1/2) or distal (p27kip1, pRb) events.
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