title: Complement activation and complement receptors on follicular dendritic cells are critical for the function of a targeted adjuvant.
abstract: A detailed understanding of how activation of innate immunity can be exploited to generate more effective vaccines is critically required. However, little is known about how to target adjuvants to generate safer and better vaccines. In this study, we describe an adjuvant that, through complement activation and binding to follicular dendritic cells (FDC), dramatically enhances germinal center (GC) formation, which results in greatly augmented Ab responses. The nontoxic CTA1-DD adjuvant hosts the ADP-ribosylating CTA1 subunit from cholera toxin and a dimer of the D fragment from Staphylococcus aureus protein A. We found that T cell-dependent, but not -independent, responses were augmented by CTA1-DD. GC reactions and serum Ab titers were both enhanced in a dose-dependent manner. This effect required complement activation, a property of the DD moiety. Deposition of CTA1-DD to the FDC network appeared to occur via the conduit system and was dependent on complement receptors on the FDC. Hence, Cr2(-/-) mice failed to augment GC reactions and exhibited dramatically reduced Ab responses, whereas Ribi adjuvant demonstrated unperturbed adjuvant function in these mice. Noteworthy, the adjuvant effect on priming of specific CD4 T cells was found to be intact in Cr2(-/-) mice, demonstrating that the CTA1-DD host both complement-dependent and -independent adjuvant properties. This is the first demonstration, to our knowledge, of an adjuvant that directly activates complement, enabling binding of the adjuvant to the FDC, which subsequently strongly promoted the GC reaction, leading to augmented serum Ab titers and long-term memory development.
authors: Department of Microbiology and Immunology, Mucosal Immunobiology and Vaccine Center, Institute of Biomedicine, University of Gothenburg, 405 30 Gothenburg, Sweden.
authors: Johan
authors: J
authors: Mattsson
authors: Ulf
authors: U
authors: Yrlid
authors: Anneli
authors: A
authors: Stensson
authors: Karin
authors: K
authors: Schön
authors: Mikael C I
authors: MC
authors: Karlsson
authors: Jeffrey V
authors: JV
authors: Ravetch
authors: Nils Y
authors: NY
authors: Lycke
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D002469:Cell Separation; D002772:Cholera Toxin / Q000138:chemical synthesis / Q000276:immunology* / Q000494:pharmacology; D003167:Complement Activation / Q000276:immunology*; D020566:Dendritic Cells, Follicular / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018858:Germinal Center / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011951:Receptors, Complement / Q000276:immunology; D017464:Receptors, Complement 3d / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000276:immunology* / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; C440610:CTA1-DD protein, recombinant; D011951:Receptors, Complement; D017464:Receptors, Complement 3d; D011993:Recombinant Fusion Proteins; D002772:Cholera Toxin