In vitro and in vivo activated T cells display increased sensitivity to PGE 2

Abstract

In this study we report that in vitro activation of T cells increased the cyclic AMP response to subsequent prostaglandin E 2 (PGE 2) stimulation severalfold per cell. This sensitization of T cells to PGE 2-induced cyclic AMP generation was observed when the T cells had been stimulated in vitro for 5 days with either the CD3 monoclonal antibody OKT3, phytohemagglutinin, or the combination phytohemagglutinin plus the phorbol ester PMA. Enhanced cyclic AMP generation following mitogenic activation was seen in response to both PGE 2 and forskolin, a direct activator of the adenylate cyclase, indicating that the amount of adenylate cyclase had increased during the in vitro activation course. In order to investigate whether various T cell subsets in general and in vivo activated T cells in particular would differ in their susceptibility to PGE 2, we isolated CD4 +, CD8 +, CD4 −CD8 −, CD4 +CD45RO + (“memory”), and CD4 +CD45RA + (“virgin”) T cells and studied PGE 2-mediated inhibition of CD3-induced proliferation, as well as cyclic AMP generation in response to PGE 2, respectively. We found that CD8 + T cells are more susceptible to PGE 2 inhibition and produce more cyclic AMP than CD4 + T cells. Double-negative T cells (enriched for γδ T cell receptor positive cells) were found to be sensitive to PGE 2 as well. Within the CD4 + T cell population, CD45RO + (“memory”) T cells were significantly more sensitive to PGE 2-mediated suppression than CD45RA + (“virgin”) T cells. CD45RO + cells required a 10-fold lower dose of PGE 2 for half-maximum suppression of proliferation. However, no difference in cyclic AMP production could be demonstrated between these two subsets. We propose that substantial heterogeneity exists among peripheral blood T lymphocyte subsets regarding their sensitivity to the immunosuppressive action of PGE 2 and that the sensitivity of individual cells changes in the course of an immune response.