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MHC Class I/Peptide Transfer between Dendritic Cells Overcomes Poor Cross-Presentation by Monocyte-Derived APCs That Engulf Dying Cells¹

Department of Gene and Cell Medicine and Institute for Immunology, Icahn Medical Institute, Mount Sinai School of Medicine, New York, NY 10029

In vivo data suggest that monocytes participate critically in cross-presentation, but other data suggest that lymph node resident dendritic cells (DCs) mainly cross-present. Here, we utilized a three-dimensional model of a blood vessel wall that endogenously supports DC development from human monocytes, and we incorporated dying autologous cells in the subendothelial matrix of the model. Flu-infected dying cells promoted monocytes to become mature DCs and cross-present cell-associated Ags for the activation of CTLs. Similar responses were induced by loading the dying cells with the TLR7/8 ligand ssRNA, whereas dying cells loaded with TLR3 ligand were less efficient. Monocyte-derived DCs that developed in this model cross-presented Ag to T cells efficiently regardless of whether they engulfed detectable amounts of labeled dying cells. Unexpectedly, the monocyte-derived cells that directly engulfed dying cells in vitro were not the major APCs stimulating CD8⁺ lymphocytes. Instead, bystander DCs acquired more robust capacity to cross-prime through receipt of MHC class I/peptide from the phagocytic, monocyte-derived cells. In mice, lymph node-homing monocyte-derived DCs processed Ags from engulfed cells and then transferred MHC class I/peptide complexes to confer cross-priming capacity to MHC class I-deficient lymph node resident CD8⁺ DCs. Thus, natural or synthetic TLR7/8 agonists contained within dying cells promote the conversion of monocytes to DCs with capacity for cross-presentation and for "cross-dressing" other DCs. These data reveal a way in which migratory monocyte-derived DCs and other DCs, like lymph node resident DCs, both mediate cross-presentation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Cancer Research Institute, National Institutes of Health Grant AI49653, and Defense Advanced Research Planning Agency contract W81XWH-04-C-0139. The prime contractor of the latter contract is the company VaxDesign. G.J.R. and Mount Sinai School of Medicine are subcontractors of this award. C.Q. later was supported by Grant JK2006A01 from the Chinese Academy of Medical Sciences.

² Address correspondence and reprint requests to Dr. Chunfeng Qu, State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences, Beijing 100021, China. E-mail address: Chunfeng.qu{at}gmail.com or Dr. Gwendalyn J. Randolph, Department of Gene and Cell Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1496, New York, NY 10029. E-mail address: Gwendalyn.Randolph{at}mssm.edu

³ Current address: State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences, Beijing 100021.

⁴ Abbreviations used in this paper: DC, dendritic cells; MHC I, MHC class I; LCL, lymphoblastoid cell line; MP, influenza A virus matrix protein; MP-LCL, lymphoblastoid cell line expressing influenza A virus matrix protein; MOI, multiplicity of infection; HA, hemagglutinin; β₂m, β₂-microglobulin.