FUNCTIONAL MATURATION OF HUMAN NAIVE T-HELPER CELLS IN THE ABSENCE OF ACCESSORY CELLS - GENERATION OF IL-4-PRODUCING T-HELPER CELLS DOES NOT REQUIRE EXOGENOUS IL-4

In the human model, requirements for the primary onset of IFN-gamma and IL-4 production in maturing T helper lymphocytes were compared. Stimulation of freshly isolated CD4(+)CD45RA(+) naive Th cells with immobilized CD3 mAb in the presence of exogenous IL-2 resulted in the proliferative response of this subset, which was equal to or higher than CD4(+)CD45RO(+) memory Th cells. Throughout the first 6 days after this mode of stimulation, naive Th cells did not secrete IL-4 and produced only small amounts of IFN-gamma, whereas high amounts of both lymphokines were secreted by stimulated autologous memory Th cells. Under these conditions, naive Th cells acquired the CD45RA(-)CD45RO(+) memory phenotype. After restimulation, such in vitro-generated CD45RO(+) cells produced high amounts of IFN-gamma but, despite the full phenotype conversion, they produced only trace amounts of IL-4. In contrast, when the primary stimulation and the expansion of cells proceeded in the presence of IL-1 beta or CD28 mAb, both IFN-gamma and IL-4 were produced after restimulation, in similar amounts compared with those produced by memory Th cells. The effect of IL-1 beta and CD28 signaling could not be obtained by the administration of exogenous IL-4 nor could the onset of IL-4 production be prevented by the presence of a neutralizing anti-IL-4 Ab in primary cultures. These data show that the development of human IL-4-producing Th cells can proceed in the absence of any pre-existing source of IL-4 and can be driven solely by the APC-related signals.