INDUCTION OF T-CELL ANERGY BY HIGH-CONCENTRATIONS OF IMMUNODOMINANT NATIVE PEPTIDE IS ACCOMPANIED BY IL-10 PRODUCTION AND A BLOCK IN JNK ACTIVITY

The ability to induce anergy in antigen-specific T cells has potential therapeutic value for altering pathologic immune responses. This stud y was undertaken to further analyze changes in cytokine production and intracellular signaling during anergy induction using high concentrat ions of native peptide ligand of tetanus toroid (TT)- and myelin basic protein (MBP)-specific human T cell lines. The TT-selected T cell lin e could be rendered unresponsive to its dominant epitope in a dose-dep endent manner (IC50 = 0.03 mu g/ml). The TT-selected line, as well as three T cell clones established from this line, continued to produce I FN-gamma and significantly increased IL-4 and IL-10 production when an ergy was induced with high concentrations of the immunodominant epitop e. JNK enzymatic activity was blocked in anergized T cells. The MBP-se lected line could likewise be rendered unresponsive by incubation with supraoptimal concentrations of immunodominant peptide and anergy indu ction was accompanied by IL-10 release. Both T cell lines could be ane rgized by the autopresentation of native peptide since anergy was indu ced in cultures lacking fresh antigen-presenting cells. This study sho ws that the mitogen-activated protein kinase cascade is blocked when a nergy is induced to high concentrations of soluble peptide. (C) 1998 A cademic Press.