GM-CSF AND IL-2 SHARE COMMON CONTROL MECHANISMS IN RESPONSE TO COSTIMULATORY SIGNALS IN T-CELLS

Antigen complexed with major histocompatibility complex class I or II molecules on the surface of antigen presenting cells interacts with th e T cell receptor (TCR) on the surface of T cells and initiates an act ivation cascade, So called costimulatory signals, mediated by other ce ll surface interactions or soluble cytokines produced by antigen prese nting cells, are also required for complete T cell activation, High le vels of cytokine gene expression in T cells also required both TCR and costimulatory signals, The granulocyte macrophage colony-stimulating factor requires sequences in the promoter as well as a powerful enhanc er located 3 kb upstream to respond to TCR-like signals, These promote r and enhancer regions are mainly activated by the transcription facto r nuclear factor of activated T cells (NFAT). The activation of NFAT b y TCR signals has been well described for interleukin-2 (IL-2) and IL- 4 gene transcription in T cells, Costimulatory signals, such as activa tion of the CD28 cell surface molecule on T cells, lead to activation through a distinct region of the granulocyte-macrophage colony-stimula ting factor (GM-CSF) promoter, This region is termed the CK-1 or CD28R E and appears to bind specific members of the NF-kappa B family of tra nscription factors, Human T leukemia virus type 1 (HTLV-1) infects T c ells and can lead to increase GM-CSF expression, We have found that th e HTLV-1 transactivator protein, tax, acts as a costimulatory signal f or GM-CSF and IL-2 gene transcription, in that it can cooperate with T CR signals to mediate high level gene expression, Tax activates the GM -CSF promoter through the CK1/CD28RE region and also activates nuclear factor-kappa B binding to this region, However, other transcription f actors or coactivators of NF-kappa B are required for tax activation b ut these remain to be identified, The CK-1/CD28RE of GM-CSF shows a hi gh degree of similarity to the IL-2 CD28RE and the IL-3 gene also cont ains a related region, This observation, together with the fact that b oth GM-CSF and IL-2 respond to TCR signals via NFAT, implies a high de gree of conservation in the regulation of cytokine gene expression in T cells.