title: A unique role of the cholera toxin A1-DD adjuvant for long-term plasma and memory B cell development.
abstract: Adjuvants have traditionally been appreciated for their immunoenhancing effects, whereas their impact on immunological memory has largely been neglected. In this paper, we have compared three mechanistically distinct adjuvants: aluminum salts (Alum), Ribi (monophosphoryl lipid A), and the cholera toxin A1 fusion protein CTA1-DD. Their influence on long-term memory development was dramatically different. Whereas a single immunization i.p. with 4-hydroxy-3-nitrophenyl acetyl (NP)-chicken γ-globulin and adjuvant stimulated serum anti-NP IgG titers that were comparable at 5 wk, CTA1-DD-adjuvanted responses were maintained for >16 mo with a half-life of anti-NP IgG ∼36 wk, but <15 wk after Ribi or Alum. A CTA1-DD dose-dependent increase in germinal center (GC) size and numbers was found, with >60% of splenic B cell follicles hosting GC at an optimal CTA1-DD dose. Roughly 7% of these GC were NP specific. This GC-promoting effect correlated well with the persistence of long-term plasma cells in the bone marrow and memory B cells in the spleen. CTA1-DD also facilitated increased somatic hypermutation and affinity maturation of NP-specific IgG Abs in a dose-dependent fashion, hence arguing that large GC not only promotes higher Ab titers but also high-quality Ab production. Adoptive transfer of splenic CD80(+), but not CD80(-), B cells, at 1 y after immunization demonstrated functional long-term anti-NP IgG and IgM memory cells. To our knowledge, this is the first report to specifically compare and document that adjuvants can differ considerably in their support of long-term immune responses. Differential effects on the GC reaction appear to be the basis for these differences.
authors.affiliation: Department of Microbiology and Immunology, Mucosal Immunobiology and Vaccine Center, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Bemark
authors.forename: Peter
authors.initials: P
authors.lastname: Bergqvist
authors.forename: Anneli
authors.initials: A
authors.lastname: Stensson
authors.forename: Anna
authors.initials: A
authors.lastname: Holmberg
authors.forename: Johan
authors.initials: J
authors.lastname: Mattsson
authors.forename: Nils Y
authors.initials: NY
authors.lastname: Lycke
mesh_terms: D000276:Adjuvants, Immunologic / Q000097:blood / Q000502:physiology*; D000534:Alum Compounds / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D017358:Cell Wall Skeleton / Q000097:blood / Q000502:physiology; D002772:Cholera Toxin / Q000097:blood* / Q000502:physiology*; D003311:Cord Factors / Q000097:blood / Q000502:physiology; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D007070:Immunoglobulin A / Q000096:biosynthesis / Q000097:blood; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D007156:Immunologic Memory; D008050:Lipid A / Q000031:analogs & derivatives / Q000097:blood / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000502:physiology; D013997:Time Factors
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; C440610:CTA1-DD protein, recombinant; D017358:Cell Wall Skeleton; D003311:Cord Factors; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D008050:Lipid A; D011993:Recombinant Fusion Proteins; C075897:Ribi adjuvant; C041524:aluminum sulfate; D002772:Cholera Toxin