The Journal of Experimental Medicine
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Published 16 December 2002. doi:10.1084/jem.20021598
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© Rockefeller University Press, 0022-1007/2002/12/1627/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 12, December 16, 2002 1627-1638
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

Laura Bonifaz1, David Bonnyay1, Karsten Mahnke1,4, Miguel Rivera1, Michel C. Nussenzweig2,3 and Ralph M. Steinman1,3

1 Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021
2 Laboratory of Molecular Immunology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021
3 Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021
4 Department of Dermatology, University of Mainz, D-55101 Mainz, Germany

Address correspondence to Ralph M. Steinman, Laboratory for Cellular Physiology and Immunology, The Rockefeller University, 1230 York Ave., Box 176, New York, NY 10021. Phone: 212-327-8106; Fax: 212-327-8875; E-mail: Steinma{at}mail.rockefeller.edu

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 {alpha}DEC-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 {alpha}DEC-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 {alpha}DEC-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 {alpha}DEC-205:OVA, induced strong immunity. The CD8+ T cells responding in the presence of agonistic {alpha}CD40 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.

Key Words: dendritic cells • DEC-205 receptor • tolerance • CD8 T cell • MHC class I


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