Costimulation of cytokine gene expression in T cells by the human T leukemia/lymphotropic virus type 1 trans activator Tax.
Many cell signals such as CD28 and CD4 binding can costimulate cytokine gene expression in activated T cells. We have found that the human T leukemia/lymphotropic virus type 1 viral protein Tax can also strongly costimulate expression of interleukin-2 (IL-2), IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA in T cells activated with the phorbol ester phorbol myristate acetate (PMA) and calcium ionophore, which can mimic activation through the antigen specific T-cell receptor. Reporter constructs also showed strong synergy between both stimuli and showed that Tax and the PMA-Ca2+ ionophore act through different regions of the IL-2 and GM-CSF genes. Furthermore, the Tax-responsive regions (TxRR) from both GM-CSF and IL-2 respond to costimulation through the CD28 surface receptor. The GM-CSF and IL-2 TxRRs showed significantly higher levels of NF-kappaB/rel binding, following induction by Tax, compared with that of the PMA-Ca2+ ionophore with only Tax capable of inducing c-Rel binding to a Consensus kappaB element within the GM-CSF TxRR. Tax protein mutants, however, showed that a pathway(s) other than NF-kappaB/rel induction could also cooperate with the PMA-Ca2+ ionophore to activate the GM-CSF and IL-2 genes. This high-level costimulation by Tax, through multiple pathways, may be important in the early stages of leukemia and in the nervous system disorder tropical spastic paraparesis.
Himes
S R
SR
Division of Human Immunology, Hanson Centre for Cancer Research, Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia.
Katsikeros
R
R
Shannon
M F
MF
D001483:Base Sequence; D018106:CD28 Antigens / Q000502:physiology; D000001:Calcimycin / Q000494:pharmacology; D002460:Cell Line; D016207:Cytokines / Q000235:genetics*; D005786:Gene Expression Regulation; D016356:Gene Products, tax / Q000502:physiology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D015375:Receptors, Interleukin-2 / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D018106:CD28 Antigens; D016207:Cytokines; D016356:Gene Products, tax; D016328:NF-kappa B; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D000001:Calcimycin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013755:Tetradecanoylphorbol Acetate