Interleukin-1 and B7/CD28 Interaction Regulate Interleukin-6 Production by Human T Cells

Production of interleukin-6 (IL-6) by the Th2 subset of murine T cells supposedly contributes to regulation of humoral immunity. Little information exists on IL-6 production by human T cells. We examined the requirements for IL-6 production by purified human blood T cells, completely depleted of IL-6-producing monocyte-accessory cells. Immobilized anti-CD3 mAb alone (coated on the culture wells) was unable to induce IL-6 production, although it could induce production of IL-2 and TNF-α. Addition of rIL-1β as an accessory signal to anti-CD3-stimulated human T cells induced IL-6 mRNA expression and protein secretion, while IL-2, IL-4, GM-CSF, IFN-γ, or TNF-α did not have any effect. In the presence of IL-1β, both CD4 + and CD8 + T cells were able to produce IL-6. We also demonstrated that phorbol 12-myristate 13-acetate (PMA) or triggering of the CD28 molecule is an effective helper signal for IL-6 production by anti-CD3-stimulated T cells. Efficient CD28 ligation was done either by anti-CD28 mAb or by binding to its natural ligand B7/BB1, presented on the 3T6 mouse fibroblast cell line coexpressing transfected human FcγRII (CD32) (to immobilize anti-CD3) and B7/BB1. Finally, we found that combinations of IL-1β with anti-CD28 mAb or PMA with anti-CD28 mAb were highly synergistic helper signals for IL-6 production. We conclude that IL-6 production by T cells is not induced by T cell receptor triggering alone, but different intracellular signaling pathways activated by IL-1β, CD28 ligation, or PMA efficiently coinduce IL-6 production.