Interleukin 7 receptor engagement stimulates tyrosine phosphorylation, inositol phospholipid turnover, proliferation, and selective differentiation to the CD4 lineage by human fetal thymocytes.
The purposes of this study were to elucidate the effects of recombinant human interleukin 7 (rhIL-7) on proliferation as well as differentiation of human fetal thymocytes and to analyze the biochemical nature of the IL-7 receptor-linked transmembrane signal. In the absence of costimulants, rhIL-7 stimulated the in vitro proliferation and colony formation of CD4+CD8+ double-positive immature fetal thymocytes. Furthermore, rhIL-7 promoted partial differentiation of immature thymocytes with a selective advantage for the development of CD4+CD8- single-positive thymocytes. Our observations suggest that IL-7 likely has an important regulatory role during the earliest stages of human T-cell ontogeny. Stimulation of fetal thymocytes with rhIL-7 resulted in enhanced tyrosine phosphorylation of three distinct phosphoproteins with molecular masses of 72, 98, 123, and 190 kDa and induced a rapid and biphasic increase in the production of inositol 1,4,5-trisphosphate, which was inhibitable by the tyrosine protein kinase inhibitor genistein. Thus, the transmembrane signal triggered by engagement of the IL-7 receptor is intimately linked to a functional tyrosine protein kinase pathway and stimulates the inositol phospholipid turnover and proliferation, as well as selective differentiation to the CD4 lineage, by human fetal thymocytes.
Uckun
F M
FM
Tumor Immunology Laboratory, University of Minnesota Health Sciences Center, Minneapolis 55455.
Tuel-Ahlgren
L
L
Obuz
V
V
Smith
R
R
Dibirdik
I
I
Hanson
M
M
Langlie
M C
MC
Ledbetter
J A
JA
D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000032:analysis*; D015704:CD4 Antigens / Q000032:analysis*; D002454:Cell Differentiation / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D004789:Enzyme Activation; D005333:Fetus; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D015851:Interleukin-7 / Q000494:pharmacology*; D007378:Interleukins / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D010716:Phosphatidylinositols / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000187:drug effects / Q000502:physiology*; D020395:Receptors, Interleukin-7; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D013950:Thymus Gland / Q000196:embryology / Q000276:immunology*; D014443:Tyrosine
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015704:CD4 Antigens; D016207:Cytokines; D015851:Interleukin-7; D007378:Interleukins; D010716:Phosphatidylinositols; D011971:Receptors, Immunologic; D020395:Receptors, Interleukin-7; D011994:Recombinant Proteins; D014443:Tyrosine; D015544:Inositol 1,4,5-Trisphosphate; D011505:Protein-Tyrosine Kinases