ANTI-CD3-ACTIVATED KILLER T-CELLS - INTERLEUKIN-6 MODULATES THE INDUCTION OF MAJOR HISTOCOMPATIBILITY COMPLEX-UNRESTRICTED CYTOTOXICITY ANDTHE EXPRESSION OF GENES-CODING FOR CYTOTOXIC EFFECTOR MOLECULES

We have investigated the role of interleukin-6 (IL-6) in the induction of major histocompatibility complex (MHC)-unrestricted cytotoxicity, as well as granzyme B, perforin, and Fas ligand gene expression, follo wing mouse T lymphocyte activation with anti-CD3 monoclonal antibody ( mAb), The generation of anti-CD3-activated killer-T (AK-T) cells was i nhibited when anti-IL-6 neutralizing mAb was added at initiation of cu lture but not 24 h later, indicating that IL-6 is involved at an early stage of AK-T cell development, However, AK-T cell induction in the p resence of exogenous IL-6 did not result in enhanced cytotoxicity, sug gesting that saturating levels of IL-6 are normally synthesized in AK- T cell cultures, The inhibitory effect of IL-6 neutralization on AK-T cell generation could not be attributed to a defect in AK-T cell proli feration or to an inability of AK-T cells to recognize and adhere to P 815 tumor target cells, However, IL-2 synthesis and CD25 expression we re downregulated in AK-T cell cultures performed in the presence of an ti-IL-6 mAb, In addition, IL-6 neutralization resulted in decreased ex pression of granzyme B and perforin, but not Fas ligand, mRNA, Exogeno us IL-2 (50 U/ml) added at initiation of culture completely reversed t he inhibitory effect of anti-IL-6 mAb on AK-T cell development, restor ing CD25 expression and tumoricidal activity, as well as granzyme B an d perforin mRNA expression, to control levels, We conclude that IL-6 m odulates AK T cell induction through an IL-2-dependent mechanism.