Regulation of cytokine production in murine helper T lymphocytes

Abstract

PGE{dollar}\sb2{dollar} is known to selectively regulate the production of Th1- and Th2-associated lymphokines. The effect of PGE{dollar}\sb2{dollar} on the production of IL-3 and GM-CSF from Th clones was examined. When stimulated with Ag and APC, IL-3/GM-CSF production from seven Th clones was differentially affected by PGE{dollar}\sb2{dollar}. A more specific bioassay confirmed that IL-3 production was differentially regulated by PGE{dollar}\sb2{dollar} in the Th clones. These data suggest that the effect of PGE{dollar}\sb2{dollar} on IL-3 production is dependent, not on a property of the lymphokine, but on a property of the T cell. When Th clones were stimulated with ionomycin alone, PGE{dollar}\sb2{dollar} enhanced IL-3/GM-CSF production from both Th1 and Th2 clones, demonstrating that the mode of stimulation affects the responsiveness to PGE{dollar}\sb2{dollar}. Addition of APC could dramatically enhance IL-3/GM-CSF production from ionomycin-stimulated Th clones. In the ionomycin-stimulated Th1 cells, PGE{dollar}\sb2{dollar} either inhibited IL-3 and GM-CSF production or had no effect, in no case was the lymphokine production enhanced by PGE{dollar}\sb2{dollar}. These data indicate that the presence of APC-derived costimulatory signals can alter the effect of PGE{dollar}\sb2{dollar} on Th lymphokine production. It has been known that LB, a B cell hybridoma, lacks a costimulatory signal to induce IL-4 from a Th2 clone F4. Addition of cholera toxin (CT) or B subunits (CTB) could enhance IL-4 production from F4 cells stimulated with Ag and LB cells. Pretreatment experiments showed that the primary target of CT was the APC, not T cells. CT-pretreated LB could enhance IL-4 from anti-CD3-stimulated F4 cells, indicating that CT mediated a costimulatory pathway to induce IL-4. In order to identify the CT-mediated costimulation, mAb were made from rats immunized with CT-pretreated LB cells. Studies of the mAb revealed that it was CTB itself that provided a costimulatory signal to induce IL-4. Interestingly, the anti-CTB mAb could inhibit IL-4 production induced by CT-pretreated LB cells. Addition of G{dollar}\sb{lcub}\rm M1{rcub}{dollar} gangliosides could not block IL-4 production induced by CT-pretreated LB cells. These data suggest that LB-associated CTB molecules are directly interacting with non-G{dollar}\sb{lcub}\rm M1{rcub}{dollar} receptors on the F4 cells. This model of CTB-mediated T-B interaction is a novel mode of regulation of IL-4 production.