Autonomous growth of lymphoid cells following IL-2 expression from retrovirus vectors containing HIV-1 trans-acting elements.
The human immunodeficiency virus type I (HIV-1) possesses powerful regulatory elements that control the rate of replication of HIV-1 and subsequent processing of HIV-1 genes. We have used this regulatory mechanism to drive expression of foreign genes inserted in retrovirus vectors. This approach was used to express the human IL-2 gene in IL-2-dependent mouse CTLL-2 cells to determine the role of autonomous growth in maintaining proliferation of virus-infected T lymphocytes during HTLV-1-induced adult T-cell leukemia (ATL). Expression of IL-2 sequences in IL-2-dependent mouse CTLL-2 cells resulted in autonomous growth of IL-2-independent CTLL-2 clones. Endogenous expression of IL-2 appeared to interrupt normal constraints of growth in that these IL-2-independent clones showed reduced cell-density-dependent inhibition but not a tumorigenic phenotype. IL-2-independent CTLL-2 clones did not secrete detectable quantities of IL-2 into culture supernatant and exhibited reduced sensitivity to the inhibitory effects of both IL-2 and IL-2 receptor antibody. These results suggest that the IL-2 autocrine loop within these cells involves intracellular IL-2/IL-2 receptor binding. The apparent lack of IL-2 production and poor responsiveness to IL-2 or IL-2 antibodies displayed by cell lines from ATL patients may be explained by an intracellular IL-2/IL-2 receptor autocrine loop.
Department of Immunology, Karolinska Institute, Stockholm, Sweden.
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Shapiro
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Meier
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Vlach
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McDonald
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Wigzell
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Stevenson
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002455:Cell Division / Q000502:physiology; D015500:Chloramphenicol O-Acetyltransferase; D002999:Clone Cells; D015756:Genes, tat / Q000235:genetics; D005822:Genetic Vectors; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D051379:Mice; D010641:Phenotype; D015375:Receptors, Interleukin-2 / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis; D012190:Retroviridae / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*; D015533:Transcriptional Activation
D000906:Antibodies; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; D015500:Chloramphenicol O-Acetyltransferase