Signals transduced through the CD4 molecule interfere with TCR/CD3-mediated ras activation leading to T cell anergy/apoptosis.
It has been previously demonstrated that the occupancy of CD4 molecules by the HIV-1 envelope glycoprotein gp120 results in marked inhibition of T cell receptor-CD3 complex (TCR/CD3) activation-induced IL-2 secretion. To elucidate the mechanism of inhibitory effects of gp160 on T cell signaling, we have investigated the intracellular biochemical events and biological output in response to anti-CD3 mAb activation of purified peripheral blood CD4+ T cells from healthy donors with and without prior exposure to HIV-1 gp160. Pretreatment with gp160 resulted in marked inhibition of tyrosine phosphorylation of p59(fyn), PLC-gamma1, ras activation, and TNF-alpha secretion in anti-CD3 mAb activated CD4+ T cells, and a subset of CD4+ cells underwent activation-induced cell death. The data presented here provide insight into the mechanism by which the interaction of HIV-1 envelope glycoproteins with CD4 molecules may alter TCR/CD3-activation-induced signal transduction resulting in anergy and apoptosis with consequent functional deficiency of CD4+ T cells.
Tamma
S M
SM
Department of Pediatrics, North Shore University Hospital-New York University School of Medicine, Manhasset, New York 11030, USA.
Chirmule
N
N
McCloskey
T W
TW
Oyaizu
N
N
Kalyanaraman
V S
VS
Pahwa
S
S
D017209:Apoptosis / Q000502:physiology; D017252:CD3 Complex / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D005786:Gene Expression Regulation; D011905:Genes, ras / Q000235:genetics*; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology; D019302:HIV Envelope Protein gp160 / Q000494:pharmacology; D015497:HIV-1; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D019014:fas Receptor / Q000096:biosynthesis
D017252:CD3 Complex; D015699:HIV Envelope Protein gp120; D019302:HIV Envelope Protein gp160; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D011505:Protein-Tyrosine Kinases