title: Engagement of CD153 (CD30 ligand) by CD30+ T cells inhibits class switch DNA recombination and antibody production in human IgD+ IgM+ B cells.
abstract: CD153 (CD30 ligand) is a member of the TNF ligand/cytokine family expressed on the surface of human B cells. Upon exposure to IL-4, a critical Ig class switch-inducing cytokine, Ag-activated T cells express CD30, the CD153 receptor. The observation that dysregulated IgG, IgA, and/or IgE production is often associated with up-regulation of T cell CD30 prompted us to test the hypothesis that engagement of B cell CD153 by T cell CD30 modulates Ig class switching. In this study, we show that IgD+ IgM+ B cells up-regulate CD153 in the presence of CD154 (CD40 ligand), IL-4, and B cell Ag receptor engagement. In these cells, CD153 engagement by an agonistic anti-CD153 mAb or T cell CD30 inhibits S mu-->Sgamma, Smu-->Salpha, and S mu-->Sepsilon class switch DNA recombination (CSR). This inhibition is associated with decreased TNFR-associated factor-2 binding to CD40, decreased NF-kappaB binding to the CD40-responsive element of the Cgamma3 promoter, decreased Igamma3-Cgamma3 germline gene transcription, and decreased expression of Ku70, Ku80, DNA protein kinase, switch-associated protein-70, and Msh2 CSR-associated transcripts. In addition, CD153 engagement inhibits IgG, IgA, and IgE production, and this effect is associated with reduced levels of B lymphocyte maturation protein-1 transcripts, and increased binding of B cell-specific activation protein to the Ig 3' enhancer. These findings suggest that CD30+ T cells modulate CSR as well as IgG, IgA, and IgE production by inducing reverse signaling through B cell CD153.
authors.affiliation: Division of Molecular Immunology, Department of Pathology, Weill Medical College of Cornell University, New York, NY 10021, USA. acerutti@med.cornell.edu
authors.forename: A
authors.initials: A
authors.lastname: Cerutti
authors.forename: A
authors.initials: A
authors.lastname: Schaffer
authors.forename: R G
authors.initials: RG
authors.lastname: Goodwin
authors.forename: S
authors.initials: S
authors.lastname: Shah
authors.forename: H
authors.initials: H
authors.lastname: Zan
authors.forename: S
authors.initials: S
authors.lastname: Ely
authors.forename: P
authors.initials: P
authors.lastname: Casali
mesh_terms: D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D001667:Binding, Competitive / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D053285:CD30 Ligand; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D018858:Germinal Center / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D007127:Immunoglobulin Constant Regions / Q000096:biosynthesis / Q000235:genetics; D007072:Immunoglobulin D / Q000096:biosynthesis*; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis*; D007137:Immunoglobulin alpha-Chains / Q000096:biosynthesis / Q000235:genetics; D007139:Immunoglobulin epsilon-Chains / Q000096:biosynthesis / Q000235:genetics; D007142:Immunoglobulin gamma-Chains / Q000096:biosynthesis / Q000235:genetics; D007148:Immunoglobulin mu-Chains / Q000096:biosynthesis / Q000235:genetics; D016130:Immunophenotyping; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000502:physiology; D017730:Ki-1 Antigen / Q000096:biosynthesis* / Q000378:metabolism; D008024:Ligands; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism; D051757:PAX5 Transcription Factor; D014066:Palatine Tonsil / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D010950:Plasma Cells / Q000276:immunology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011401:Promoter Regions, Genetic / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D011506:Proteins / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism; D011995:Recombination, Genetic / Q000276:immunology*; D012097:Repressor Proteins; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology; D015533:Transcriptional Activation / Q000276:immunology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
chemical_list: D018106:CD28 Antigens; D053285:CD30 Ligand; D019013:CD40 Antigens; D016207:Cytokines; D004268:DNA-Binding Proteins; D007127:Immunoglobulin Constant Regions; D007072:Immunoglobulin D; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007137:Immunoglobulin alpha-Chains; D007139:Immunoglobulin epsilon-Chains; D007142:Immunoglobulin gamma-Chains; D007148:Immunoglobulin mu-Chains; D017730:Ki-1 Antigen; D008024:Ligands; D008562:Membrane Glycoproteins; D009687:Nuclear Proteins; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D012097:Repressor Proteins; D047992:TNF Receptor-Associated Factor 2; C505716:TNFRSF4 protein, human; C505774:TNFSF8 protein, human; D014157:Transcription Factors; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; C087042:PRDM1 protein, human; D023201:CD40 Ligand; D015847:Interleukin-4; D000074462:Positive Regulatory Domain I-Binding Factor 1