OPPOSING EFFECTS OF TGF-BETA(2) ON THE TH1 CELL-DEVELOPMENT OF NAIVE CD4(-CELLS ISOLATED FROM DIFFERENT MOUSE STRAINS() T)

The development of naive dense CD4(+) T cells from different mouse str ains toward Th1 cells, as monitored by measuring secondary IFN-gamma p roduction, was affected by TCF-beta(2) in a differential way. Th1 cell development of naive CD4(+) T cells from strains C57Bl/6, BALB/c, and NMRI primed by immobilized anti-CD3 mAb was strongly inhibited in the presence of TGF-beta(2). Even when the Th1 cell-inducer IL-12 was add ed, the same effect of TGF-beta(2) was observed. In contrast, Th1 deve lopment was substantially promoted by TCF-beta(2) with T cells from C3 H/He and CPA/J mice. Further analyses using CD4(+) T cells from (C57Bl /6xCBA/J)F-1 hybrids or DBA/1 mice showed that Th1 development was inh ibited by TGF-beta(2) if the T cells were activated by anti-CD3 mAb, b ut it was enhanced upon costimulation with anti-CD28 mAb. Determinatio n of primary IL-2 production revealed that T cells from (C57Bl/6xCBA/J )F-1 and DBA/1 mice produced low amounts of IL-2 following stimulation by anti-CD3 mAb alone and comparatively high amounts after coactivati on by anti-CD28 mAb. In the presence of TGF-beta(2), the production of IL-2 was completely suppressed if such T cells were activated solely by anti-CD3 mAb, but it was only partially inhibited after costimulati on by anti-CD28 mAb. Furthermore, TCF-beta(2)-promoted Th1 development of such T cells was strongly inhibited after neutralization of endoge nously produced IL-2 and completely restored by the addition of human IL-2. Thus, our results indicate that the TCF-beta(2)-mediated stimula tion of Th1 cell development requires the presence of relatively high concentrations of IL-2. Therefore, the opposing effect of TGF-beta(2) on the Th1 cell development of naive CD4(+) T cells from different mou se strains appearsto be the result of the variable potency of the resp ective CD4(+) T cells to produce IL-2 in the presence of TCF-beta(2).