Distinct roles of the phosphatidylinositol 3-kinase and STAT5 pathways in IL-7-mediated development of human thymocyte precursors.
Here, we define the IL-7R-activated signal that promotes survival and proliferation of T cell progenitors and demonstrate that it is distinct from the signals that induce differentiation. We show that IL-7 activates PKB and STAT5 in human thymocytes. Into T cell precursors we introduced chimeric receptors with a cytoplasmic domain of the IL-7R that is no longer able to activate PI-3K/PKB and STAT5 and tested the transduced cells in a fetal thymic organ culture. We also examined the T cell precursor activity of progenitors expressing dominant-negative forms of PI-3K or STAT5B. These experiments revealed that PI-3K/PKB activation is essential for the survival and proliferation of T cell precursors and suggest that STAT5 activated by IL-7 mediates T cell differentiation.
Pallard
C
C
Division of Immunology, The Netherlands Cancer Institute, Antoni van Leeuwenhoekhuis, Amsterdam.
Stegmann
A P
AP
van Kleffens
T
T
Smart
F
F
Venkitaraman
A
A
Spits
H
H
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D005333:Fetus; D006801:Humans; D015851:Interleukin-7 / Q000494:pharmacology*; D008894:Milk Proteins; D009924:Organ Culture Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D020395:Receptors, Interleukin-7 / Q000037:antagonists & inhibitors / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D050799:STAT5 Transcription Factor; D013234:Stem Cells / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology* / Q000196:embryology; D015534:Trans-Activators / Q000502:physiology*
D000906:Antibodies; D004268:DNA-Binding Proteins; D015851:Interleukin-7; D008894:Milk Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020395:Receptors, Interleukin-7; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; C494095:STAT5B protein, human; C494097:Stat5b protein, rat