title: Dendritic cell maturation is required for the cross-tolerization of CD8+ T cells.
abstract: In vivo models have shown that tissue-restricted antigen may be captured by bone marrow-derived cells and cross-presented for the tolerization of CD8+ T cells. Although these studies have shown peripheral tolerization of CD8+ T cells, the mechanism of antigen transfer and the nature of the antigen-presenting cell (APC) remain undefined. We report here the establishment of an in vitro system for the study of cross-tolerance and show that dendritic cells (DCs) phagocytose apoptotic cells and tolerize antigen-specific CD8+ T cells when cognate CD4+ T helper cells are absent. Using this system, we directly tested the "two-signal" hypothesis for the regulation of priming versus tolerance. We found that the same CD83+ myeloid-derived DCs were required for both cross-priming and cross-tolerance. These data suggested that the current model for peripheral T cell tolerance, "signal 1 in the absence of signal 2", requires refinement: the critical checkpoint is not DC maturation, but instead the presence of a third signal, which is active at the DC-CD4+ T cell interface.
authors.affiliation: Laboratory of Neuro-Oncology, The Rockefeller University, 1230 York Avenue, Box 26, New York, NY 10021, USA. albertm@rockvax.rockefeller.edu
authors.forename: M L
authors.initials: ML
authors.lastname: Albert
authors.forename: M
authors.initials: M
authors.lastname: Jegathesan
authors.forename: R B
authors.initials: RB
authors.lastname: Darnell
mesh_terms: D000069594:Abatacept; D017951:Antigen Presentation; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology; D000956:Antigens, Viral / Q000276:immunology; D017209:Apoptosis; D018106:CD28 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen; D002450:Cell Communication; D002454:Cell Differentiation; D002478:Cells, Cultured; D018920:Coculture Techniques; D018592:Cross-Over Studies; D017077:Culture Media, Conditioned / Q000737:chemistry; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D018796:Immunoconjugates; D007136:Immunoglobulins / Q000276:immunology; D007375:Interleukin-1 / Q000494:pharmacology; D018664:Interleukin-12 / Q000032:analysis / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology; D018448:Models, Immunological; D009975:Orthomyxoviridae / Q000276:immunology; D010587:Phagocytosis; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D000097802:CD83 Antigen
chemical_list: D000069594:Abatacept; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000956:Antigens, Viral; D018106:CD28 Antigens; D019013:CD40 Antigens; D023201:CD40 Ligand; D060908:CTLA-4 Antigen; D017077:Culture Media, Conditioned; D006684:HLA-DR Antigens; D018796:Immunoconjugates; D007136:Immunoglobulins; D007375:Interleukin-1; D018664:Interleukin-12; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D000097802:CD83 Antigen; C556706:CTLA4 protein, human