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

被引:1029
作者
Bonifaz, L
Bonnyay, D
Mahnke, K
Rivera, M
Nussenzweig, MC
Steinman, RM
机构
[1] Rockefeller Univ, Cellular Physiol & Immunol Lab, New York, NY 10021 USA
[2] Rockefeller Univ, Lab Mol Immunol, New York, NY 10021 USA
[3] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA
[4] Rockefeller Univ, Chris Browne Ctr Immunol & Immune Dis, New York, NY 10021 USA
[5] Johannes Gutenberg Univ Mainz, Dept Dermatol, D-55101 Mainz, Germany
关键词
dendritic cells; DEC-205; receptor; tolerance; CD8 T cell; MHC class I;
D O I
10.1084/jem.20021598
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 cxDEC-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 aDEC-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 cxDEC-205:OVA, induced strong immunity. The CD8(+) T cells responding in the presence of agonistic cxCD40 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.
引用
收藏
页码:1627 / 1638
页数:12
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