EARLY ACTIVATION SIGNAL-TRANSDUCTION PATHWAYS OF TH1 AND TH2 CELL CLONES STIMULATED WITH ANTI-CD3 - ROLES OF PROTEIN-TYROSINE KINASES IN THE SIGNAL FOR IL-2 AND IL-4 PRODUCTION

In the present experiments, TCR-CD3-associated early activation signal transduction pathways were examined in Th1 and Th2 clones by the stim ulation with soluble monovalent anti-CD3 which resulted in efficient p roduction of IL-2 and IL-4 in Th1 and Th2 cells, respectively. Althoug h protein tyrosine kinases such as Fyn and ZAP-70 were activated in Th 1 clones shortly after stimulation, these kinases in Th2 clones were n ot activated; but, their activity in resting conditions was shown to b e decreased by the stimulation. In accordance with these findings, nei ther phospholipase C-gamma 1 activation nor phosphatidyl inositol-4,5- bisphosphate breakdown was induced in Th2 clones, in contrast to posit ive responses in Th1 clones. The oscillation of intracellular free Ca2 + concentration ([Ca2+](i)) was a common signal for the activation of both Th1 and Th2 clones; however, the [Ca2+](i) elevation in Th1 clone s was herbimycin A sensitive, whereas that in Th2 was clone resistant, suggesting that the mechanism of the [Ca2+](i) elevation in Th2 cells is different from that in Th1 cells in terms of the participation of protein tyrosine kinases. The anti-CD3 stimulation did not cause Lck a ctivation in either the Th1 or Th2 clone, although remarkable activati on was induced in both clones following anti-CD4 stimulation, indicati ng that Lck activation was not required for either IL-2 or IL-4 produc tion of Th cells. Taken together, these results indicate that Th1 and Th2 cells are different from each other in early activation signal tra nsduction pathways, especially in the role of protein tyrosine kinases .