Stimulated plasmacytoid dendritic cells impair human T-cell development.
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-alpha/beta is responsible for this inhibitory effect. Consistent with this notion, we show that exogenously added IFN-alpha 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 TCRbeta 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-alpha. It is evident from our data that IFN-alpha 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 (p27(kip1), pRb) events.
Schmidlin
Heike
H
Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Dontje
Wendy
W
Groot
Fedde
F
Ligthart
Suzanne J
SJ
Colantonio
Arnaud D
AD
Oud
Monique E
ME
Schilder-Tol
Esther J
EJ
Spaargaren
Marcel
M
Spits
Hergen
H
Uittenbogaart
Christel H
CH
Blom
Bianca
B
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D015851:Interleukin-7 / Q000378:metabolism; D051379:Mice; D010950:Plasma Cells / Q000166:cytology / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism*
D000906:Antibodies; D015703:Antigens, CD; D007370:Interferon Type I; D015851:Interleukin-7; D011948:Receptors, Antigen, T-Cell; D020395:Receptors, Interleukin-7; D011494:Protein Kinases