MODULATORY EFFECT OF AGGREGATING THE CD3-MOLECULAR COMPLEX ON T-CELL ACTIVATION

The role of cross-linking the TCR CD3 complex in the induction of T cell activation was examined using human peripheral blood T cells and the Jurkat leukemic T cell line. IL-2 production was induced from these cells by pulsing them with mAb to CD3 and costimulating with phorbol myristate acetate (PMA). Cross-linking the anti-CD3 mAb with soluble goat anti-mouse immunoglobulin (GaMIg) markedly inhibited IL-2 production by these cells. Soluble GaMIg did not induce a generalized inhibition of IL-2 production as it was required for responses induced by mAb to class I MHC molecules. In addition, cross-linking anti-CD3 mAb with GaMIg did not inhibit IL-2 production induced by PMA and ionomycin. Inhibition of IL-2 production induced by soluble GaMIg reflected diminished accumulation of mRNA for IL-2. By contrast, immobilized GaMIg was a potent stimulus for IL-2 production by T cells pulsed with anti-CD3 mAb and costimulated with PMA. Cross-linking anti-CD3 with soluble GaMIg induced enhanced aggregation of the ligated molecules, but it did not alter the profile of the change in intracellular calcium induced. To determine whether cross-linking of mAb played a role in inducing IL-2 production as well as in limiting responsiveness, F(ab) fragments were employed. F(ab) fragments of anti-CD3 mAb failed to induce IL-2 production by PMA costimulated Jurkat cells. However, cross-linking of anti-CD3 F(ab)-pulsed Jurkat cells with low concentrations of soluble GaMIg induced IL-2 production in the presence of PMA, whereas higher concentrations suppressed responses. The data indicate that induction of IL-2 production requires aggregation of the TCR CD3 complex, whereas excessive cross-linking diminishes the induction of IL-2 production. Moreover, the results indicate that various biologic activities of the CD3 molecular complex, including aggregation, signaling capability, and the ability to induce IL-2 gene transcription, are differentially affected by cross-linking. © 1992.