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A Unique Role of the Cholera Toxin A1-DD Adjuvant for Long-Term Plasma and Memory B Cell Development

Artikel i vetenskaplig tidskrift
Författare Mats Bemark
Peter Bergqvist
Anneli Stensson
Anna Holmberg
Johan Mattsson
Nils Y Lycke
Publicerad i Journal of Immunology
Volym 186
Nummer/häfte 3
Sidor 1399-1410
ISSN 0022-1767
Publiceringsår 2011
Publicerad vid Institutionen för biomedicin, avdelningen för mikrobiologi och immunologi
Sidor 1399-1410
Språk en
Länkar dx.doi.org/10.4049/jimmunol.1002881
Ämneskategorier Immunologi inom det medicinska området

Sammanfattning

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.

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