REQUIREMENT FOR DISTINCT JANUS KINASES AND STAT PROTEINS IN T-CELL PROLIFERATION VERSUS IFN-GAMMA PRODUCTION FOLLOWING IL-12 STIMULATION

While IL-12 is known to activate JAK2 and TYK2 and induce the phosphor ylation of STAT4 and STAT3, little is known regarding how the activati on of these signaling molecules is related to the biologic effects of IL-12, Using an IL-12-responsive T cell clone (2D6), we investigated t heir requirements for proliferation and IFN-gamma production of 2D6 ce lls, 2D6 cells could be maintained with either IL-12 or IL-2. 2D6 line s maintained with IL-12 (2D6(IL-12)) Or IL-2 (2D6(IL-2)) exhibited com parable levels of proliferation, but produced large or only small amou nts of IFN-gamma, respectively, when restimulated with IL-12 after sta rvation of either cytokine, 2D6(IL-12) induced TYK2 and STAT4 phosphor ylation. In contrast, their phosphorylation was marginally induced in 2D6(IL-2). The reduced STAT4 phosphorylation was due to a progressive decrease in the amount of STAT4 protein along with the passages in IL- 2-containing medium. 2D6(IL-12). The 2D6(IL-2) similarly proliferating in response to IL-12 induced comparable levels of JAK2 activation and STAT5 phosphorylation, JAK2 was associated with STAT5, and IL-12-indu ced STAT5 phosphorylation was elicited in the absence of JAK3 activati on. These results indicate that IL-12 has the capacity to induce/maint ain STAT4 and STAT5 proteins, and that TYK2 and JAK2 activation correl ate with STAT4 phosphorylation/IFN-gamma induction and STAT5 phosphory lation/cellular proliferation, respectively.