gp160 of HIV or anti‐CD4 monoclonal antibody ligation of CD4 induces inhibition of JNK and ERK‐2 activities in human peripheral CD4⁺ T lymphocytes

Abstract

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 proliferation and interleukin (IL)-2 production in human CD4+ T cells, in an MHC-independent way. We have previously shown that this inhibition was associated with a diminished binding activity of the IL-2 transcription factors NF-AT, NF-kappaB, and AP-1. AP-1 plays a key role in the regulation of IL-2 transcription, and ERK and JNK activities are necessary for regulating AP-1 at both the transcriptional and the post-transcriptional levels. We therefore studied, in human peripheral CD4+ T cells, the regulation of the activities of extracellular signal-regulated protein kinases (ERK) and c-Jun N-terminal kinases (JNK) by two CD4 ligands, gp160 the envelope glycoprotein of human immunodeficiency virus (HIV) and an anti-CD4 monoclonal antibody (mAb). Pre-incubation of CD4+ T lymphocytes in the presence of anti-CD4 mAb or gp160 inhibits the activation of JNK in response to phorbol 12-myristate 13-acetate and ionomycin. In the same conditions, phosphorylation and activation of ERK-2 were also inhibited. Inhibition of both JNK and ERK-2 activities 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 ligands.

Relative Resistance in the Development of T Cell Anergy in CD4+ T Cells from Simian Immunodeficiency Virus Disease-Resistant Sooty Mangabeys

“…Interestingly, we did not see any difference in ERK stimulation in seropositive vs seronegative sooty mangabeys (Fig. 7 and data not shown), although it has been reported that ligation of CD4 by HIV-derived gp160 inhibits ERK stimulation (79,80) and seropositive sooty mangabeys harbor high viral loads (81) and therefore an abundance of SIV-derived gp160. This data would indicate that the potential differences in T cell signaling within CD4 ϩ T cells from sooty mangabey may contribute to the SIV disease-free phenotype of this species, although a more detailed study of the precise pathway by which this results in anergy resistance and/or IL-2 transcription remains to be elucidated.…”

Cutting Edge: CD4 Is the Receptor for the Tick Saliva Immunosuppressor, Salp15

“…However, Salp15 did not induce Lck phosphorylation in the absence of T cell stimulation, in contrast to the described effect of gp120 (23). Moreover, Salp15 does not affect AP-1 DNA-binding activity (3) or TCR-mediated ERK activation (data not shown) compared with the ERK-mediated inhibition of AP-1 DNA-binding activity observed in cells treated with gp120 (24), further distinguishing the effect of Salp15 to those of HIV gp120 and anti-CD4 cross-linking.…”

A Therapeutic CD4 Monoclonal Antibody Inhibits TCR-ζ Chain Phosphorylation, ζ-Associated Protein of 70-kDa Tyr319 Phosphorylation, and TCR Internalization in Primary Human T Cells

“…For example, inhibition of the formation of signal transduction complexes, such as those formed between p120 GAP , phospholipase C-␥ 1 and other molecules (40), calcium signals (41,42), Erk-2 and c-Jun N-terminal kinase activation (43,44,63), and transcription factor activation (44,45) would all be expected in the event that TCR-phosphorylation and ZAP-70 recruitment were inhibited. The present work extends previous reports on the inhibition of signaling complexes by showing that TCR-induced Vav (Fig.…”