Modulation of Bcl-2 protein by CD4 cross-linking: a possible mechanism for lymphocyte apoptosis in human immunodeficiency virus infection and for rescue of apoptosis by interleukin-2.
We have previously demonstrated that CD4 cross-linking (CD4XL) results in apoptosis of CD4+ T cells and augmentation of Fas antigen (CD95, APO-1) expression in CD4+ and CD8+ T cells. Here we demonstrate that CD4XL mediated by both, anti-CD4 monoclonal antibody (MoAb) or human immunodeficiency virus (HIV) envelope protein gp120 reduces the expression of the proto-oncogene Bcl-2 in CD4+ T cells, but not in CD8+ T cells, concurrently with the induction of CD4+ T cell-apoptosis. Additionally, the Bcl-2dim population expressed high levels of Fas antigen. Bax, an antagonist of Bcl-2, was brightly expressed even in the Bcl-2dim population. Addition of interleukin (IL)-2 rescued CD4+ T cells from CD4XL-induced Bcl-2 downmodulation and apoptosis induction. These results support the hypothesis that CD4 ligation by HIV-1 envelope protein in vivo in HIV-infected patients selectively reduces Bcl-2 protein in CD4+ T lymphocytes, thereby facilitating Fas/Fas-ligand triggered apoptosis; furthermore the findings reported expand the rationale for use of IL-2 in HIV disease.
Hashimoto
F
F
Department of Pediatrics, North Shore University Hospital-New York University School of Medicine, Manhasset 11030, USA.
Oyaizu
N
N
Kalyanaraman
V S
VS
Pahwa
S
S
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015704:CD4 Antigens / Q000276:immunology / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D002478:Cells, Cultured; D005434:Flow Cytometry; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D011485:Protein Binding; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D051028:bcl-2-Associated X Protein
D000911:Antibodies, Monoclonal; C494826:BAX protein, human; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D007376:Interleukin-2; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein