title: CD40 expressed on thymic epithelial cells provides costimulation for proliferation but not for apoptosis of human thymocytes.
abstract: Human thymic epithelial cells express CD40, so we examined the possible role of CD40 in activation of thymocytes. We observed that both CD4+CD8- and CD4-CD8+ thymocytes proliferate after stimulation by anti-CD3 mAb in the presence of cultured thymic epithelial cells. Costimulation of CD4+ thymocytes by thymic epithelial cells is partly inhibited by an anti-CD40 mAb, but this mAb has no effect on costimulation of CD8+ thymocytes. The selective costimulatory ability of CD40 for CD4+ thymocytes was confirmed in experiments in which thymocytes were stimulated with anti-CD3 in the presence of murine P815 cells transfected with CD40 cDNA. The level of costimulation induced by P815-CD40 was comparable with that induced by P815 cells expressing CD80 (B7.1). Treatment of thymocytes with the Ca2+ ionophore ionomycin and the phorbol ester PMA or with anti-CD3 mAb resulted in up-regulation of the CD40 ligand, suggesting that this molecule is involved in CD40-mediated costimulation of human thymocytes. Costimulation of thymocytes by CD80 strongly increased anti-CD3-induced death of fetal thymocytes. In contrast, costimulation by CD40 did not increase anti-CD3-mediated apoptosis of these thymocytes. To confirm that CD40 does not affect anti-CD3-induced cell death, we established a variant of the Jurkat T leukemic cell line that constitutively expresses CD40L and analyzed the sensitivity of this cell line for activation-induced apoptosis. In contrast to CD80, CD40 failed to increase anti-CD3-mediated apoptosis in CD40L+ Jurkat cells, whereas both CD40 and CD80 strongly increased IL-2 production induced by anti-CD3. These findings suggest that costimulation by CD40 is involved in clonal expansion of CD4+ thymocytes but not in activation-induced cell death.
authors.affiliation: Division of Immunology of the Netherlands Cancer Institute, Amsterdam.
authors.forename: G
authors.initials: G
authors.lastname: Ruggiero
authors.forename: E
authors.initials: E
authors.lastname: Martinez Cáceres
authors.forename: A
authors.initials: A
authors.lastname: Voordouw
authors.forename: E
authors.initials: E
authors.lastname: Noteboom
authors.forename: D
authors.initials: D
authors.lastname: Graf
authors.forename: R A
authors.initials: RA
authors.lastname: Kroczek
authors.forename: H
authors.initials: H
authors.lastname: Spits
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D018122:B7-1 Antigen / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism* / Q000502:physiology*; D023201:CD40 Ligand; D016923:Cell Death / Q000276:immunology; D002675:Child, Preschool; D004848:Epithelium / Q000276:immunology / Q000378:metabolism; D005333:Fetus; D006801:Humans; D007223:Infant; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D015458:Leukemia, T-Cell; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; D017252:CD3 Complex; D019013:CD40 Antigens; D008562:Membrane Glycoproteins; D018799:Intercellular Adhesion Molecule-1; D023201:CD40 Ligand