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
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- Laura Bonifaz
- 1Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021
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- David Bonnyay
- 1Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021
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- Karsten Mahnke
- 1Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021
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- Miguel Rivera
- 1Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021
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- Michel C. Nussenzweig
- 2Laboratory of Molecular Immunology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021
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- Ralph M. Steinman
- 1Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021
抄録
<jats:p>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 αDEC-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 αDEC-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 αDEC-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 αDEC-205:OVA, induced strong immunity. The CD8+ T cells responding in the presence of agonistic αCD40 antibody produced large amounts of interleukin 2 and interferon γ, 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.</jats:p>
収録刊行物
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- The Journal of Experimental Medicine
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The Journal of Experimental Medicine 196 (12), 1627-1638, 2002-12-16
Rockefeller University Press
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詳細情報 詳細情報について
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- CRID
- 1362544419683235072
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- NII論文ID
- 30017416959
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- ISSN
- 15409538
- 00221007
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