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Dendritic Cell Targeting of Survivin Protein in a Xenogeneic Form Elicits Strong CD4⁺ T Cell Immunity to Mouse Survivin¹

Laboratory of Cellular Physiology and Immunology, Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021

To determine whether strong CD4⁺ T cell immunity could be induced to a nonmutated self protein that is important for tumorigenesis, we selectively targeted the xenogeneic form of survivin, a survival protein overexpressed in tumors, to maturing dendritic cells in lymphoid tissues. Dendritic cell targeting via the DEC205 receptor in the presence of anti-CD40 and poly(I:C) as maturation stimuli, induced strong human and mouse survivin-specific CD4⁺ T cell responses, as determined by IFN-, TNF-, and IL-2 production, as well as the development of lytic MHC class II-restricted T cells and memory. Immunity was enhanced further by depletion of CD25⁺foxp3⁺ cells before vaccination. anti-DEC205-human survivin was superior in inducing CD4⁺ T cell responses relative to other approaches involving survivin plasmid DNA or survivin peptides with adjuvants. However, we were unable to induce CD8⁺ T cell immunity to survivin by two doses of DEC205-targeted survivin or the other strategies. Therefore, significant CD4⁺ T cell immunity to a self protein that is overexpressed in most human cancers can be induced by DEC205 targeting of the Ag in its xenogeneic form to maturing DCs.

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 National Institutes of Health Grants AI10313 and 5P01AI051573.

² Address correspondence and reprint requests to Dr. Ralph M. Steinman, Laboratory of Cell Physiology and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10021. E-mail address: steinma{at}mail.rockefeller.edu

³ Abbreviations used in this paper: BM, bone marrow; DC, dendritic cell; MHC-I, MHC class I; hsurvivin, human survivin; msurvivin, mouse survivin; CHO, Chinese hamster ovary; BMDC, BM-derived DC; ICS, intracellular cytokine staining; hTERT, human telomerase reverse transcriptase; CEA, carcinoembryonic Ag.

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