title: Synchronization of dendritic cell activation and antigen exposure is required for the induction of Th1/Th17 responses.
abstract: The dendritic cell (DC) targeting/activation patterns required to elicit Th1/Th17 responses remain undefined. One postulated requirement was that of a physical linkage between Ags and immunomodulators. Accordingly, the separate same-site administration of Ag85B-ESAT-6 (hybrid-1 protein; H1), a mycobacterial fusion Ag, and the CAF01 liposome-based adjuvant induced similar Ab and weak Th2 responses as those of coformulated H1/CAF01 but failed to elicit Th1/Th17 responses. Yet, this separate same-site injection generated the same type and number of activated Ag(+)/adjuvant(+) DCs in the draining lymph nodes (LN) as that of protective H1/CAF01 immunization. Thus, targeting/activating the same DC population by Ag and adjuvant is not sufficient to elicit Th1/Th17 responses. To identify the determinants of Th1/Th17 adjuvanticity, in vivo tracking experiments using fluorescently labeled Ag and adjuvant identified that a separate same-site administration elicits an additional early Ag(+)/adjuvant(-) DC population with a nonactivated phenotype, resulting from the earlier targeting of LN DCs by H1 than by CAF01 molecules. This asynchronous targeting pattern was mimicked by the injection of free H1 prior to or with, but not after, H1/CAF01 or H1/CpG/ aluminum hydroxide immunization. The injection of soluble OVA similarly prevented the induction of Th1 responses by OVA/CAF01. Using adoptively transferred OT-2 cells, we show that the Ag targeting of LN DCs prior to their activation generates nonactivated Ag-pulsed DCs that recruit Ag-specific T cells, trigger their initial proliferation, but interfere with Th1 induction in a dose-dependent manner. Thus, the synchronization of DC targeting and activation is a critical determinant for Th1/Th17 adjuvanticity.
authors.affiliation: World Health Organization Collaborating Center for Vaccinology and Neonatal Immunology, Department of Pathology-Immunology, Medical Faculty of the University of Geneva, Geneva 1211, Switzerland.
authors.forename: Arun T
authors.initials: AT
authors.lastname: Kamath
authors.forename: Béatris
authors.initials: B
authors.lastname: Mastelic
authors.forename: Dennis
authors.initials: D
authors.lastname: Christensen
authors.forename: Anne-Françoise
authors.initials: AF
authors.lastname: Rochat
authors.forename: Else Marie
authors.initials: EM
authors.lastname: Agger
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Pinschewer
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
authors.forename: Paul-Henri
authors.initials: PH
authors.lastname: Lambert
authors.forename: Claire-Anne
authors.initials: CA
authors.lastname: Siegrist
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D019264:Adoptive Transfer; D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D032581:Tuberculosis Vaccines / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; C557979:Ag85B-ESAT-6 fusion antigen; D018984:Epitopes, T-Lymphocyte; D011993:Recombinant Fusion Proteins; D032581:Tuberculosis Vaccines