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

• Published in: Blood 2013-01, Vol.121 (1), p.85-94
• Main Authors: Pihlgren, Maria, Silva, Alberto B., Madani, Rime, Giriens, Valérie, Waeckerle-Men, Ying, Fettelschoss, Antonia, Hickman, David T., López-Deber, María Pilar, Ndao, Dorin Mlaki, Vukicevic, Marija, Buccarello, Anna Lucia, Gafner, Valérie, Chuard, Nathalie, Reis, Pedro, Piorkowska, Kasia, Pfeifer, Andrea, Kündig, Thomas M., Muhs, Andreas, Johansen, Pål
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Vesicular Transport - deficiency; Adaptor Proteins, Vesicular Transport - genetics; Adaptor Proteins, Vesicular Transport - physiology; Adoptive Transfer; Amino Acid Sequence; Amyloid beta-Peptides - administration & dosage; Amyloid beta-Peptides - immunology; Animals; Antigen Presentation; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Biological and medical sciences; CD28 Antigens - deficiency; CD28 Antigens - immunology; CD40 Ligand - deficiency; CD40 Ligand - immunology; Germinal Center - immunology; Hematologic and hematopoietic diseases; Histocompatibility Antigens Class II - immunology; Humans; Immunoglobulin Class Switching - immunology; Immunoglobulin G - biosynthesis; Immunoglobulin M - biosynthesis; Lipopolysaccharide Receptors - immunology; Liposomes; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Molecular Sequence Data; Ovalbumin - administration & dosage; Ovalbumin - immunology; Peptide Fragments - administration & dosage; Peptide Fragments - immunology; Receptors, Antigen, B-Cell - immunology; T-Lymphocytes - immunology; Toll-Like Receptor 4 - deficiency; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - physiology; Vaccination; Vaccines, Subunit - administration & dosage; Vaccines, Subunit - immunology
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2012-02-413831

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. •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.