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 cytokin e gene expression in activated T cells, We have found that the human T leukemia/lymphotropic virus type 1 viral protein Tax can also strongl y costimulate expression of interleukin-2 (IL-2), IL-3, and granulocyt e-macrophage colony-stimulating factor (GM-CSF) mRNA in T cells activa ted 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 throug h 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 costim ulation through the CD28 surface receptor, The GM-CSF and IL-2 TxRRs s howed significantly higher levels of NF-kappa B/rel binding, following induction by Tax, compared with that of the PMA-Ca2+ ionophore with o nly Tax capable of inducing c-Rel binding to a consensus KB element wi thin the GM-CSF TxRR. Tax protein mutants, however, showed that a path way(s) other than NF-kappa B/rel induction could also cooperate with t he PMA-Ca2+ ionophore to activate the GM-CSF and IL-2 genes. This high -level costimulation by Tax, through multiple pathways, may be importa nt in the early stages of leukemia and in the nervous system disorder tropical spastic paraparesis.