Distinct signals are required for proliferation and lymphokine gene expression in murine T cell clones.
Experiments were performed to assess the capacity of lectin (Con A), ionomycin, phorbol ester (PMA), and recombinant IL 2 to mediate proliferation as well as the expression of cell surface IL 2 receptors, two lymphokine genes, IL 2 and IFN-gamma, and the c-myc proto-oncogene in cloned T cell populations. Stimulation of T cell clones with recombinant IL 2 resulted in proliferation and sustained expression of the c-myc cellular proto-oncogene, but did not induce the expression of mRNA for the lymphokines IFN-gamma and IL 2. In contrast, stimulation of cloned T cells with lectin alone induced significant IFN-gamma and IL 2 mRNA expression, up-regulation of the number of cell surface IL 2 receptors, and transient c-myc expression. Ionomycin alone was not a sufficient signal for lymphokine mRNA induction. The phorbol ester PMA alone induced neither proliferation nor lymphokine gene expression but potentiated lectin and ionomycin-mediated signals. We also performed experiments to examine whether the T cell response to extracellular stimuli was a function of the activation state of the cell. Reexposure of 48-hr antigen-activated cloned cells to identical stimuli revealed several differences. Low but significant levels of IFN-gamma mRNA were now also reinduced in activated clones cells in response to IL 2 or PMA alone. Activated cells were refractory to reinduction of IL 2 mRNA by any stimulus, which may reflect a physiologic mechanism to limit clonal expansion after antigenic stimulation. This could be partially reversed by restimulation with lectin in the presence of cycloheximide, suggesting a role for a labile protein repressor in the down-regulation of IL 2 mRNA expression. PMA alone induced an IL 2-independent proliferative response. We demonstrate that distinct signals are required for lymphokine gene expression vs cellular proliferation in cloned T lymphocyte populations, and that the capacity of extracellular stimuli to reinduce expression of lymphokine genes or to mediate cell proliferation is altered by prior activation.
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte; D000954:Antigens, Surface / Q000032:analysis; D002460:Cell Line; D003208:Concanavalin A; D004987:Ethers / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics / Q000494:pharmacology; D015759:Ionomycin; D008213:Lymphocyte Activation / Q000187:drug effects; D008222:Lymphokines / Q000235:genetics*; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D011971:Receptors, Immunologic / Q000378:metabolism; D015375:Receptors, Interleukin-2; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000945:Antigens, Differentiation, T-Lymphocyte; D000954:Antigens, Surface; D004987:Ethers; D007376:Interleukin-2; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2; D003208:Concanavalin A; D015759:Ionomycin; D007371:Interferon-gamma; D013755:Tetradecanoylphorbol Acetate