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Selection of an Antibody Library Identifies a Pathway to Induce Immunity by Targeting CD36 on Steady-State CD8⁺ Dendritic Cells¹

Elisa Tagliani^*, Pierre Guermonprez, Jorge Sepúlveda^*, María López-Bravo, Carlos Ardavín, Sebastian Amigorena, Federica Benvenuti^2,3,* and Oscar R. Burrone^2,3,*

^* International Centre for Genetic Engineering and Biotechnology, Trieste, Italy; U653 Institut National de la Santé et de la Recherche Médicale Institut Curie, Paris, France; and Department of Immunology and Oncology, Centro National de Biotecnologia/Consejo Superior de Investigaciones Cientificas, Universidad Autónoma de Madrid, Madrid, Spain

Improvement of the strategy to target tumor Ags to dendritic cells (DCs) for immunotherapy requires the identification of the most appropriate ligand/receptor pairing. We screened a library of Ab fragments on mouse DCs to isolate new potential Abs capable of inducing protective immune responses. The screening identified a high-affinity Ab against CD36, a multi-ligand scavenger receptor primarily expressed by the CD8⁺ subset of conventional DCs. The Ab variable regions were genetically linked to the model Ag OVA and tested in Ag presentation assays in vitro and in vivo. Anti-CD36-OVA was capable of delivering exogenous Ags to the MHC class I and MHC class II processing pathways. In vivo, immunization with anti-CD36-OVA induced robust activation of naive CD4⁺ and CD8⁺ Ag-specific T lymphocytes and the differentiation of primed CD8⁺ T cells into long-term effector CTLs. Vaccination with anti-CD36-OVA elicited humoral and cell-mediated protection from the growth of an Ag-specific tumor. Notably, the relative efficacy of targeting CD11c/CD8⁺ via CD36 or DEC205 was qualitatively different. Anti-DEC205-OVA was more efficient than anti-CD36-OVA in inducing early events of naive CD8⁺ T cell activation. In contrast, long-term persistence of effector CTLs was stronger following immunization with anti-CD36-OVA and did not require the addition of exogenous maturation stimuli. The results identify CD36 as a novel potential target for immunotherapy and indicate that the outcome of the immune responses vary by targeting different receptors on CD8⁺ 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 "Associazione Italiana per la Ricerca sul Cancro." E.T. was supported by an International Centre for Genetic Engineering and Biotechnology Predoctoral Fellowship from the Corso di Perfezionamento of the Scuola Normale Superiore di Pisa. F.B. was supported by an International Centre for Genetic Engineering and Biotechnology Postdoctoral Fellowship.

² These authors contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Federica Benvenuti and Dr. Oscar R. Burrone, International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34012 Trieste, Italy. E-mail addresses: benvenut{at}icgeb.org and burrone{at}icgeb.org

⁴ Abbreviations used in this paper: DC, dendritic cell; BMDC, bone marrow-derived DC; LN, lymph node; scFv, single chain fragments; SIP, small immunoprotein; RT, room temperature; PFA, paraformaldehyde; ctrl, control.

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