Blood Journal
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TLR4- and TRIF-dependent stimulation of B lymphocytes by peptide liposomes enables T cell–independent isotype switch in mice

  1. Maria Pihlgren1,
  2. Alberto B. Silva1,
  3. Rime Madani1,
  4. Valérie Giriens1,
  5. Ying Waeckerle-Men2,
  6. Antonia Fettelschoss2,
  7. David T. Hickman1,
  8. María Pilar López-Deber1,
  9. Dorin Mlaki Ndao1,
  10. Marija Vukicevic1,
  11. Anna Lucia Buccarello1,
  12. Valérie Gafner1,
  13. Nathalie Chuard1,
  14. Pedro Reis1,
  15. Kasia Piorkowska1,
  16. Andrea Pfeifer1,
  17. Thomas M. Kündig2,
  18. Andreas Muhs1,*, and
  19. Pål Johansen2,*
  1. 1AC Immune SA, Parc Scientifique EPFL B, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland; and
  2. 2Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

Key Points

  • Peptide assemblies on MPLA-containing liposomes induce IgG responses independent of T cells, CD40L, CD28, CD14, and MyD88.

  • Direct stimulation of B cells through TLR4 and TRIF is required for T cell–independent IgG responses.

Abstract

Immunoglobulin class switching from IgM to IgG in response to peptides is generally T cell–dependent and vaccination in T cell–deficient individuals is inefficient. We show that a vaccine consisting of a dense array of peptides on liposomes induced peptide-specific IgG responses totally independent of T-cell help. Independency was confirmed in mice lacking T cells and in mice deficient for MHC class II, CD40L, and CD28. The IgG titers were high, long-lived, and comparable with titers obtained in wild-type animals, and the antibody response was associated with germinal center formation, expression of activation-induced cytidine deaminase, and affinity maturation. The T cell–independent (TI) IgG response was strictly dependent on ligation of TLR4 receptors on B cells, and concomitant TLR4 and cognate B-cell receptor stimulation was required on a single-cell level. Surprisingly, the IgG class switch was mediated by TIR-domain-containing adapter inducing interferon-β (TRIF), but not by MyD88. This study demonstrates that peptides can induce TI isotype switching when antigen and TLR ligand are assembled and appropriately presented directly to B lymphocytes. A TI vaccine could enable efficient prophylactic and therapeutic vaccination of patients with T-cell deficiencies and find application in diseases where induction of T-cell responses contraindicates vaccination, for example, in Alzheimer disease.

  • Submitted February 27, 2012.
  • Accepted October 12, 2012.
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