title: Reduced antigen concentration and costimulatory blockade increase IFN-gamma secretion in naive CD8+ T cells.
abstract: CD8+ T cells are killer cells but also major producers of IFN-gamma. We have investigated the effects of peptide antigen titration and costimulatory blockade on IFN-gamma production and proliferation by naive CD8+ T cells. Mature dendritic cells (DC) pulsed with high amounts of agonist peptide triggered proliferation but little IFN-gamma secretion in individual T cells. In contrast, immature DC pulsed with similar amounts of peptide induced IFN-gamma secretion in a larger fraction of T cells but triggered less proliferation. Blocking B7.2 or lowering the amount of peptide on mature DC led to a response similar to that induced by immature DC, suggesting that differences in stimulatory strength were responsible for the different responses. Using splenic antigen-presenting cells (APC) we demonstrate that reducing the amount of peptide in combination with B7 blockage enhanced IFN-gamma secretion and decreased proliferation in naive CD8+ T cells in an additive way. Our data suggest that IFN-gamma secretion and proliferation are independently and inversely controlled by stimulatory strength in naive CD8+ T cells. This may enable CD8+ T cells to respond with IFN-gamma secretion to immature APC with few peptide ligands consistent with an early immunoregulatory role of CD8+ T cells.
authors.affiliation: Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Håkan T L
authors.initials: HT
authors.lastname: Hall
authors.forename: Jelena
authors.initials: J
authors.lastname: Petrovic
authors.forename: Petter
authors.initials: P
authors.lastname: Höglund
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology / Q000494:pharmacology*; D018122:B7-1 Antigen / Q000276:immunology*; D051940:B7-2 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D015847:Interleukin-4 / Q000276:immunology / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D014758:Viral Core Proteins / Q000276:immunology / Q000494:pharmacology*; D014764:Viral Proteins / Q000276:immunology / Q000494:pharmacology*
chemical_list: D015703:Antigens, CD; D000956:Antigens, Viral; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D014758:Viral Core Proteins; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus; C102366:nucleoprotein (366-374), influenza virus; D015847:Interleukin-4; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor