Studies on the activation of normal murine T cell clones of the Th 1 type have shown that two signals are required to stimulate the cells to make interleukin-2 (IL-2) and divide. One signal is given through the antigen-specific receptor, which is uniquely expressed on each clone. The other signal is called costimulation and is delivered through the CD28 receptor, which is expressed in the same form on all mouse T cells. One major objective for the past two years has been to discover the molecular basis for costimulation. Using an antibody against CD28 to mimic costimulation and an antibody against the ~ chain of T cell receptor to mimic antigenic stimulation, we have studied the way in which costimulation synergizes with T cell receptor occupancy to enhance IL-2 production. In the absence of costimulation 2x10-4 T cells secrete about 0.2 units of Il-2. In the presence of anti-CD28 antibody the amount increases hundred-fold. T cells clones were stably transfected with reporter constructs containing the murine IL-2 enhancer/promoter region joined to a luciferase gene in order to examine the effects of costimulation on PNA transcriptor. Although antibody to the T cell antigen-receptor luciferase production substantially, in such transfectants, addition of anti-CD28 antibody gave no further increase, suggesting that costimulation does not augment IL-2 production by increasing the rate of transcription. The stability of Il-2 messenger RNA was then examined by stimulating the cells for 4 hours and stopping transcription with cyclosporin A. Activation D could not be used as it was found to artificially stabilize IL-2 message on its own. Under these conditions. mRNA with anti-T cell receptor antibody stimulation was found to be relatively unstable with a half-life of 30 minutes of anti-CD28 significantly stabilize the mRNA, preventing degradation for at least one hour, followed by decay with a half-life of 30-40 minutes. Integration of the mRNA decay curves in one experiment suggested that the different stabilities could fully account for the difference in IL-2 accumulation with and without anti-CD28 over that same time period. Thus, the major effect of costimulation through the CD28 receptor appears to be to increase the stability of the IL-2 message.
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