Selection of an antibody library identifies a pathway to induce immunity by targeting CD36 on steady-state CD8 alpha+ dendritic cells.
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 CD8alpha+ 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/CD8alpha+ 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 CD8alpha+ DCs.
Tagliani
Elisa
E
International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
Guermonprez
Pierre
P
Sepúlveda
Jorge
J
López-Bravo
María
M
Ardavín
Carlos
C
Amigorena
Sebastian
S
Benvenuti
Federica
F
Burrone
Oscar R
OR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000502:physiology*; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D018955:CD36 Antigens / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D016827:CD8 Antigens / Q000096:biosynthesis*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D045142:Cross-Priming / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D004705:Endocytosis / Q000235:genetics / Q000276:immunology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D007140:Immunoglobulin Fab Fragments / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology / Q000378:metabolism; D019151:Peptide Library; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
D000911:Antibodies, Monoclonal; D018955:CD36 Antigens; D016827:CD8 Antigens; C431698:CD8alpha antigen; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007140:Immunoglobulin Fab Fragments; D019151:Peptide Library; D011993:Recombinant Fusion Proteins; D010047:Ovalbumin