title: Involvement of CD4 D3-D4 membrane proximal extracellular domain for the inhibitory effect of oxidative stress on activation-induced CD4 down-regulation and its possible role for T cell activation.
abstract: During antigen presentation, CD4 functions to stabilize T cell receptor (TCR)-class II MHC interactions and coordinate Ag-induced T cell activation signals. These activation signals cause CD4 down-regulation, presumably acting to optimize T cell activation. We previously reported that oxidative stress interferes with activation-induced CD4 down-regulation in T cells. In this study, we have further investigated inhibition of CD4 down-regulation by oxidative stress and its role for T cell activation. A construct comprised of the mouse FcgammaRIIB extracellular domain and the transmembrane/cytoplasmic domains of human CD4 (FcgammaR/CD4) was expressed in a human T cell line. Oxidant actually potentiated down-regulation of the FcgammaR/CD4 chimera and induced Lck dissociation from both CD4 and FcgammaR/CD4, which is a crucial intracellular process for activation-induced CD4 down-regulation, suggesting a critical role of CD4 ectodomain in the inhibition of CD4 down-regulation by oxidative stress. Furthermore, insertion of CD4 D3-D4 membrane proximal extracellular region between FcgammaR extracellular domain and CD4 transmembrane/cytoplasmic domains in FcgammaR/CD4 chimera made this molecule behave like native CD4 molecule under oxidative stress condition. These data imply that the inhibitory effect of oxidative stress on CD4 down-regulation is executed via D3-D4 domain of CD4 ectodomain. As to its role for T cell activation, CD4 coaggregation with CD3 under the oxidative conditions enhanced activation signal induced by CD3 aggregation. Our results demonstrate that Ag-induced T cell activation which is normally concomitant with CD4 down-regulation may be disturbed through the aberrant regulation of CD4 expression by oxidative stress.
authors.affiliation: Department of Immunology and Immunopathology, Kagawa Medical University, 1750-1 Ikenobe, Miki, Kita-gun, 761-0793, Kagawa, Japan. immunol@kms.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Nakamura
authors.forename: K
authors.initials: K
authors.lastname: Yube
authors.forename: A
authors.initials: A
authors.lastname: Miyatake
authors.forename: J C
authors.initials: JC
authors.lastname: Cambier
authors.forename: M
authors.initials: M
authors.lastname: Hirashima
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000235:genetics; D015704:CD4 Antigens / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D008969:Molecular Sequence Data; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D017434:Protein Structure, Tertiary; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D015704:CD4 Antigens; C080571:Fc gamma receptor IIB; D016877:Oxidants; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D014443:Tyrosine; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D011493:Protein Kinase C