The effects of CD3, CD4 and CD28 signaling on lymphocytes during human immunodeficiency virus-1 infection.
We investigated the effects of early human immunodeficiency virus-1 infection (HIV-1) on CD4- and CD28-mediated co-signaling of the T cell receptor (TCR)/CD3 complex in peripheral blood lymphocytes (PBL). CD4 ligation either alone or in conjunction with TCR occupancy resulted in abrogated signaling shown by impaired co-association of the tyrosine kinase ZAP-70 with the CD3-zeta chains in virally infected PBL. In addition, down-regulation of CD4-associated TCR signaling resulted in diminished tyrosine phosphorylation of mitogen-activated protein kinase (MAPK), a serine threonine kinase which is critically involved in the regulation of transcription factors. Furthermore, these aberrant CD4-driven signals rendered HIV-1-infected PBL susceptible to activation-induced cell death. By contrast, cross-linking of the TCR/CD3 complex with the CD28 receptor improved tyrosine phosphorylation of MAPK and salvaged infected PBL from activation-induced cell death. Our data demonstrate the importance of appropriate CD3, CD4 and CD28 co-stimulatory function to prevent apoptosis. The CD4-mediated signaling defects of the TCR could contribute to the loss of immunocompetent cells during HIV-1 infection via activation-induced cell death, whereas stimulation through the CD28 pathway could reverse these detrimental effects.
Guntermann
C
C
Department of Immunology, St. Bartholomew's and the Royal London School of Medicine and Dentistry, London, GB.
Zheng
R
R
Nye
K E
KE
D017209:Apoptosis / Q000276:immunology; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002470:Cell Survival; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015497:HIV-1; D006801:Humans; D066298:In Vitro Techniques; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D014443:Tyrosine / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase
D018106:CD28 Antigens; D017252:CD3 Complex; D015704:CD4 Antigens; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D017871:Calcium-Calmodulin-Dependent Protein Kinases