GP160 OF HIV OR ANTI-CD4 MONOCLONAL-ANTIBODY LIGATION OF CD4 INDUCES INHIBITION OF JNK AND ERK-2 ACTIVITIES IN HUMAN PERIPHERAL CD4(-LYMPHOCYTES() T)

Under physiological conditions, activation of CD4(+) T cells by major histocompatibility complex (MHC)antigen complexes requires engagement of both the T cell receptor and the CD4 molecule. However, CD4 ligands binding to the CD4 molecule has also been shown to inhibit T cell pro liferation and interleukin (IL)-2 production in human CD4(+) T cells, in an MHC-independent way. We have previously shown that this inhibiti on was associated with a diminished binding activity of the IL-2 trans cription factors NF-AT, NF-chi B, and AP-1. AP-1 plays a key role in t he regulation of IL-2 transcription, and ERK and JNK activities are ne cessary for regulating AP-1 at both the transcriptional and the post-t ranscriptional levels. We therefore studied, in human peripheral CD4() T cells, the regulation of the activities of extracellular signal-re gulated protein kinases (ERK) and c-Jun N-terminal kinases (JNK) by tw o CD4 ligands, gp160 the envelope glycoprotein of human immunodeficien cy virus (HIV) and an anti-CD4 monoclonal antibody (mAb). Pre-incubati on of CD4(+) T lymphocytes in the presence of anti-CD4 mAb or gp160 in hibits the activation of JNK in response to phorbol 12-myristate 13-ac etate and ionomycin. In the same conditions, phosphorylation and activ ation of ERK-2 were also inhibited. Inhibition of both JNK and ERK-2 a ctivities are specific for binding of CD4 ligands to the CD4 molecule. They were not observed in CD8(+) T lymphocytes. These results suggest that a specific inhibition of JNK and ERK-2 activities contributes to defective IL-2 production in T lymphocytes pre-incubated with CD4 lig ands.