Anti-CD28 antibody- and IL-4-induced human T cell proliferation is sensitive to rapamycin

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Abstract
Rapamycin (RAPA) is a potent immunosuppressant. In this study we investigated the effect of RAPA on T cell proliferation triggered by various stimuli in an in vitro human model. The proliferation of T cells stimulated via an alternative pathway using phorbol myristate acetate (PMA) and anti-CD28 antibody (αCD28) in the absence of antigen-presenting cells (APC) was strongly inhibited by RAPA. T cell proliferation provoked via a combination of CD3/TCR and CD28 pathways using anti-CD3 antibody (αCD3) plus αCD28 was also inhibited by RAPA in the presence of APC. The mitogen (phytohaemagglutinin (PHA) or αCD3)-induccd up-regulation of expression of the IL-2 receptor a chain (IL-2Rα) and the IL-4 receptor (IL-4R) was sensitive to RAPA. This suggests that RAPA's interference with the IL-2 and IL-4 autocrine loops during T cell activation might contribute to RAPA's overall immunosuppressive effect. We have further demonstrated in a two-stage culture system that RAPA strongly inhibited IL-4-stimulated proliferation of T cells, the latter being either pretreated with αCD3 in the presence of APC, or with PMA plus αCD28 in the absence of APC. The result suggests that the Ca++ influx during the pretreatment is not obligatory for T cells to achieve IL-4 responsiveness. The results also indicate that RAPA's antiproliferative effect on IL-4-stimulated T cells is not contingent on the various mechanisms of cell priming. Therefore, RAPA's major target is probably at the second stage after the priming. Our study has extended current knowledge about the effect of RAPA on human T cells.