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Langerhans Cells Derived from Genetically Modified Human CD34⁺ Hemopoietic Progenitors Are More Potent Than Peptide-Pulsed Langerhans Cells for Inducing Antigen-Specific CD8⁺ Cytolytic T Lymphocyte Responses¹

Jianda Yuan^*,,||, Jean-Baptiste Latouche^2,,¶,||, John L. Reagan^*,,||, Glenn Heller^,||,#, Isabelle Riviere^,¶,||,#, Michel Sadelain^,¶,||,# and James W. Young^3,*,,,||,#

^* Laboratory of Cellular Immunobiology; Allogeneic Bone Marrow Transplantation and Clinical Immunology Services; Division of Hematologic Oncology, Department of Medicine; Biostatistics Service, Department of Biostatistics and Epidemiology; and ^¶ Laboratory of Gene Transfer and Gene Expression, Gene Transfer and Somatic Cell Engineering Facility, Immunology Program, ^|| Memorial Sloan-Kettering Cancer Center; and ^# Weill Medical College of Cornell University; New York, NY 10021

Sustained Ag expression by human dendritic cells (DCs) is an attractive means of optimizing Ag presentation for stimulating durable cellular immunity. To establish proof of principle, we used Langerhans cell (LC) progeny of retrovirally transduced CD34⁺ hemopoietic progenitor cells to stimulate responses against the HLA-A*0201-restricted influenza matrix peptide (fluMP). Retroviral transduction of CD34⁺ hemopoietic progenitor cells, during pre-expansion by thrombopoietin, c-kit ligand, and FLT-3 ligand, on recombinant fibronectin, but in the absence of FCS, resulted in gene expression by 20–30% of the LCs. Expression persisted at least 28 days, with little decline (<30%) over that time. Retroviral transduction did not alter the phenotype or potent immunogenicity of normal mature DCs. FluMP-transduced LCs stimulated a 130-fold expansion of T cells reactive with HLA-A*0201-fluMP tetramers, even at LC:T cell ratios of 1:100–150 and lower, whereas fluMP-pulsed LCs stimulated only a 30-fold expansion. FluMP-transduced LCs also stimulated higher IFN- secretion (100–123 spot-forming cells/10⁵ CD8⁺ T cells) than did fluMP-pulsed LCs (10–91 spot-forming cells/10⁵ CD8⁺ T cells). CD8⁺ T cells stimulated by transduced LCs did not react preferentially with retrovirally transduced targets, indicating that the responses targeted only the immunizing influenza and not the retroviral vector Ags, even though these could have provided nonspecific helper epitopes presented by the transduced LCs. These data demonstrate that gene-transduced LCs maintain the activated phenotype as well potent immunogenicity typical of mature DCs. LCs genetically modified to express fluMP are also more potent stimulators of Ag-specific CD8⁺ T cell responses than are peptide-pulsed LCs.

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				J. Yuan, J.-B. Latouche, J. Hodges, A. N. Houghton, G. Heller, M. Sadelain, I. Riviere, and J. W. Young Langerhans-Type Dendritic Cells Genetically Modified to Express Full-Length Antigen Optimally Stimulate CTLs in a CD4-Dependent Manner J. Immunol., February 15, 2006; 176(4): 2357 - 2365. [Abstract] [Full Text] [PDF]