title: Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance.
abstract: To identify endocytic receptors that allow dendritic cells (DCs) to capture and present antigens on major histocompatibility complex (MHC) class I products in vivo, we evaluated DEC-205, which is abundant on DCs in lymphoid tissues. Ovalbumin (OVA) protein, when chemically coupled to monoclonal alphaDEC-205 antibody, was presented by CD11c+ lymph node DCs, but not by CD11c- cells, to OVA-specific, CD4+ and CD8+ T cells. Receptor-mediated presentation was at least 400 times more efficient than unconjugated OVA and, for MHC class I, the DCs had to express transporter of antigenic peptides (TAP) transporters. When alphaDEC-205:OVA was injected subcutaneously, OVA protein was identified over a 4-48 h period in DCs, primarily in the lymph nodes draining the injection site. In vivo, the OVA protein was selectively presented by DCs to TCR transgenic CD8+ cells, again at least 400 times more effectively than soluble OVA and in a TAP-dependent fashion. Targeting of alphaDEC-205:OVA to DCs in the steady state initially induced 4-7 cycles of T cell division, but the T cells were then deleted and the mice became specifically unresponsive to rechallenge with OVA in complete Freund's adjuvant. In contrast, simultaneous delivery of a DC maturation stimulus via CD40, together with alphaDEC-205:OVA, induced strong immunity. The CD8+ T cells responding in the presence of agonistic alphaCD40 antibody produced large amounts of interleukin 2 and interferon gamma, acquired cytolytic function in vivo, emigrated in large numbers to the lung, and responded vigorously to OVA rechallenge. Therefore, DEC-205 provides an efficient receptor-based mechanism for DCs to process proteins for MHC class I presentation in vivo, leading to tolerance in the steady state and immunity after DC maturation.
authors.affiliation: Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Bonifaz
authors.forename: David
authors.initials: D
authors.lastname: Bonnyay
authors.forename: Karsten
authors.initials: K
authors.lastname: Mahnke
authors.forename: Miguel
authors.initials: M
authors.lastname: Rivera
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Steinman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology; D017951:Antigen Presentation; D000941:Antigens / Q000276:immunology*; D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism*; D039521:CD11c Antigen / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004705:Endocytosis; D005260:Female; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007108:Immune Tolerance; D037181:Lectins, C-Type; D008198:Lymph Nodes / Q000166:cytology; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D010047:Ovalbumin / Q000276:immunology; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D015703:Antigens, CD; D039521:CD11c Antigen; D019013:CD40 Antigens; D002352:Carrier Proteins; C093569:DEC-205 receptor; D015395:Histocompatibility Antigens Class I; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; D010047:Ovalbumin