ANERGIC T-CELLS ARE DEFECTIVE IN BOTH JUN NH2-TERMINAL KINASE AND MITOGEN-ACTIVATED PROTEIN-KINASE SIGNALING PATHWAYS

T helper type 1 cells (Th1) become anergic when stimulated through the antigen receptor in the absence of costimulation. They do not produce IL-2 or proliferate in response to subsequent stimulation. Previous s tudies have indicated that anergic T cells are defective in the transa ctivational activity of the transcription factor, AP-1, which is requi red for optimal IL-2 transcription. Using two murine Th1 cell clones, we demonstrate that anergic Th1 cells have defects in both jun NH2-ter minal kinase (JNK) and extracellular signal-regulated kinase (ERK) act ivities. These kinases have been shown to be important for the upregul ation of AP-1 activity. Furthermore, our data show that ERK and JNK ac tivities are restored when anergy is induced in the presence of the pr otein synthesis inhibitor cycloheximide, or when anergic T cells are a llowed to proliferate in response to exogenous IL-2. These treatments have previously been shown to prevent or reverse the anergic state. Ou r results suggest that defects in both JNK and ERK may result in the d ecreased AP-1 activity and the reduced IL-2 transcription observed in anergic T cells.