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Langerhans-Type Dendritic Cells Genetically Modified to Express Full-Length Antigen Optimally Stimulate CTLs in a CD4-Dependent Manner¹

Jianda Yuan^*,¶, Jean-Baptiste Latouche^2,¶,#, Joanna Hodges^¶,#, Alan N. Houghton^,,¶,**,, Glenn Heller^||,, Michel Sadelain^¶,#,**,, Isabelle Riviere^¶,#,**, and James W. Young^3,*,,,¶,

^* Laboratory of Cellular Immunobiology, Laboratory of Tumor Immunology, Allogeneic Blood and Marrow Transplantation and Clinical Immunology Services, ^¶ Division of Hematologic Oncology, Department of Medicine, ^|| Biostatistics Service, Department of Biostatistics and Epidemiology, ^# 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

Oncoretroviral vectors encoding either full-length Ag or a corresponding immunodominant peptide were expressed in Langerhans-type dendritic cells (LCs) differentiated from CD34⁺ progenitors. We used human CMV as a model Ag restricted by HLA-A*0201 to define parameters for eventual expression of cancer Ags by LCs for active immunization against tumors. Stimulation by CMVpp65_495–503-pulsed LCs, CMVpp65_495–503-transduced LCs, and full-length CMVpp65-transduced LCs respectively increased tetramer-reactive T cells with an effector memory phenotype by 10 ± 11, 34 ± 21, and 51 ± 24-fold (p < 0.05) from CMV-seropositive donors. CMV-specific CD8⁺ CTLs achieved respective frequencies of 231 ± 102, 583 ± 219, and 714 ± 281 spot-forming cells per 10⁵ input cells (p < 0.01) in ELISPOT assays for IFN- secretion. LCs expressing full-length Ag stimulated greater lytic activity than either peptide-transduced or peptide-pulsed LCs (p < 0.05), all in the absence of exogenous cytokines. pp65-transduced LCs presenting class I and II MHC-restricted epitopes expanded IFN--secreting CD4⁺ T cells, whereas pp65_495–503-transduced LCs did not. CD4⁺ T cell numbers even declined after stimulation by pp65_495–503 peptide-pulsed LCs. CD4⁺ T cell depletion confirmed their contribution to the more robust CTL responses. LCs, transduced with a retroviral vector encoding full-length Ag, stimulate potent CTLs directed against multiple epitopes in a CD4⁺ Th cell-dependent manner.